Benutzerin:Kersti Nebelsiek/16

Leuzismus

Loci

DogSpotKITednrb.pdf

• EDNRB (Endothelinrezeptor)
• SOX10
• PAX3
• MITF - microphthalmia-associated transcription factor
• KIT (Maus: c-kit, belly-spot, dominant spotting, spotted sterile male, Steel Factor Receptor, Dominant white spotting, c-kit proto-oncogene protein)
• steel locus, encoding MGF
• Analysis of the Inheritance of White Spotting and the Evaluation of KIT and EDNRB as Spotting Loci in Dutch Boxer Dogs
• In humans, mutations in SOX10, PAX3, and MITF are responsible for different types of the Waardenburg-Shah syndrome that is associated with sensorineural deafness and white forelock
• In inbred mice it has been shown that this gene (*steel locus, encoding MGF) or a gene in the direct vicinity is a major recessive modifier of white spotting in Ednrb s/Ednrbs mice. Remarkably, one allele of this locus is semidominant and is associated with the penetrance and expressivity of a white forelock phenotype, similar to that seen in our SS group of boxers.
• With the genomic map of the dog soon available, it should be possible to elucidate the molecular basis of white spotting in the boxer and in many other dog breeds.

• M. A. E. VAN HAGEN,J.VAN DER KOLK,M.A.M.BARENDSE,S.IMHOLZ,P.A.J.LEEGWATER, B. W. KNOL, AND B. A. VAN OOST : Analysis of the Inheritance of White Spotting and the Evaluation of KIT and EDNRB as Spotting Loci in Dutch Boxer Dogs Journal of Heredity 2004:95(6):526–531 a 2004, The American Genetic Association doi:10.1093/jhered/esh083

CollieSpotting.pdf

• Exclusion of EDNRBand KITas the basis for white spotting in Border Collies

• Danika Metallinos und Jasper Rine: Exclusion of EDNRBand KITas the basis for white spotting in Border Collies GenomeBiology2000, 1(2):research0004.1–0004.4 http://genomebiology.com/2000/1/2/research/0004.1

Pax3 - paired box gene 3

paired box gene 3

PAX3/FKHR fusion

paired domain gene 3

paired domain gene HuP2

paired box homeotic gene 3

One in a family of Pax genes involved in regulating embryonic development at the level of transcription. The Pax3 gene is on chromosome 2 in band q35. It encodes a DNA-binding transcription factor that is expressed in the early embryo.

Mutation of Pax3 leads to Waardenburg syndrome with a wide bridge of the nose; pigmentary disturbances such as two different colored eyes, white forelock and eyelashes and premature graying of the hair; and some degree of nerve deafness.

The syndrome is named for a Dutch eye doctor named Petrus Johannes Waardenburg (1886-1979) who first noticed that people with differently colored eyes often had a hearing impairment. Pax3 is also known as WS1 (for Waardenberg syndrome I).

PAX3 paired box gene 3 (Waardenburg syndrome 1) [ Homo sapiens ]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=5077

This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini.

CRANIOFACIAL-DEAFNESS-HAND SYNDROME; CDHS

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=122880

1. 122880 Links

CRANIOFACIAL-DEAFNESS-HAND SYNDROME; CDHS Gene map locus 2q35 TEXT

A number sign (#) is used with this entry because craniofacial-deafness-hand syndrome is caused by mutation in the PAX3 gene (606597).

Sommer et al. (1983) reported a syndrome in mother and infant daughter with features of flat facial profile, hypertelorism, hypoplastic nose with slitlike nares, and a sensorineural hearing loss. Common radiologic findings included small maxilla, absent or small nasal bones, and ulnar deviation of the hands.

Because dystopia canthorum, a midfacial alteration, is the most reliable indicator of a PAX3 mutation among Waardenburg syndrome type I families (193500), according to Farrer et al. (1994), and because during murine development the Pax3 gene was expressed in the nasal process (Goulding et al., 1991), Asher et al. (1996) explored the possibility that a mutant allele of PAX3 might be responsible for CDHS. In the mother and child reported by Sommer et al. (1983), Asher et al. (1996) found a heterozygosity for a asn47-to-lys missense mutation (606597.0010) in the paired domain of PAX3 using SSCP analysis followed by sequencing. A C-to-G transversion was responsible for the amino acid substitution. A previously described missense mutation in the same codon (asn47-to-his; 606597.0011) was reported by Hoth et al. (1993) in association with Waardenburg syndrome type III. A substitution of a basic amino acid for asparagine at residue 47, conserved in all known murine Pax and human PAX genes, appears to have a more drastic effect on the phenotype than missense, frameshift, and deletion mutations of PAX3 that cause Waardenburg syndrome type I. Among 24 unrelated individuals with WS1 mutations, no 2 had been found to have the same point mutation in the protein-coding region of PAX3, nor did they have a change in the same codon (Farrer et al., 1994). The finding in CDHS provided the first opportunity to compare molecular pathology and clinical heterogeneity between 2 different mutations in the same codon for PAX3.

Sommer and Bartholomew (2003) provided a follow-up of the family reported by Sommer et al. (1983). A boy born 2 years after the birth of the index patient had precisely the same manifestations as his mother and sister. The mother and daughter were found to have congenital absence of nasolacrimal ducts. The sister and brother grew and developed normally, were very good students, and were active in sports. They were attending college and had goals to be a veterinary technician and a computer technologist, respectively.

RHABDOMYOSARCOMA 2; RMS2

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=268220

1. 268220 Links

RHABDOMYOSARCOMA 2; RMS2 Alternative titles; symbols

RHABDOMYOSARCOMA, ALVEOLAR; RMSA

Gene map locus 1p36.2-p36.12, 13q14.1, 2q35 TEXT

A number sign (#) is used with this entry because of evidence that alveolar rhabdomyosarcoma results from fusion of the PAX3 gene (606597) on chromosome 2 with the FKHR gene (136533) on chromosome 13 as a result of a translocation t(2;13), or from fusion of the PAX7 gene (167410) on chromosome 1 with the FKHR gene as a result of a translocation t(1;13).

Douglass et al. (1987) found a specific translocation, t(2;13)(q35;q14), in 5 cases of advanced rhabdomyosarcoma. It was identified directly in cells that had metastasized from bone marrow in 1 patient, and in xenografts derived from the tumors of 4 other patients. Wang-Wuu et al. (1988) did chromosomal analysis of 16 rhabdomyosarcomas (4 primary tumors and 12 tumors after nude mouse passage). Of 7 alveolar tumors, 4 had t(2;13)(q37;q14); in 2 of these it was the only structural abnormality. Eight of 9 embryonal tumors had trisomy 2. In a rhabdomyosarcoma of the eyelid present at birth, Hayashi et al. (1988) found a translocation t(2;8)(q37;q13). They considered that the region 2q37 may be important in the development of this neoplasm. The tumor had features of embryonal rhabdomyosarcoma with no features typical of alveolar structures. Thus, there appear to be 2 loci involved in rhabdomyosarcoma: one on chromosome 11 (see 268210) and one on chromosome 2. By a physical mapping strategy, Barr et al. (1991) delimited the rhabdomyosarcoma t(2;13) breakpoint to a narrow region of chromosome 13. Shapiro et al. (1992) demonstrated that the FLT oncogene (165070), previously localized to 13q12 by in situ hybridization, is located proximal to the chromosome 13 breakpoint and is not a target for disruption by the tumor specific translocation t(2;13). Shapiro et al. (1992) and Barr et al. (1992) gave the breakpoint in chromosome 2 as q35 and the breakpoint in chromosome 13 as q14. Barr et al. (1992) compared the location of the breakpoint on chromosome 2 with the breakpoints in other cell lines and, by a comparison with the linkage map of the syntenic region on mouse chromosome 1, concluded that the t(2;13) breakpoint is probably most closely flanked by loci INHA (147380) and ALPI (171740). Barr et al. (1993) determined that PAX3 (606597), which had previously been found to be mutated in Waardenburg syndrome, was affected by a t(2;13)(q35;q14) translocation associated with alveolar rhabdomyosarcoma. The rearrangement breakpoints occurred within an intron downstream of the paired box and homeodomain-encoding regions. Upstream PAX3 sequences hybridized to a novel transcript in t(2;13)-containing lines. Galili et al. (1993) demonstrated that the chromosome 13 gene that is fused with PAX3 is a member of the 'forkhead' domain family (FKHR).

Bennicelli et al. (1996) studied the mechanism for transcriptional gain of function resulting from a PAX3-FKHR fusion.

Among primary rhabdomyosarcoma tumors, Anderson et al. (2001) found that 37 had t(2;13)/PAX3-FKHR, 8 had t(1;13) PAX7-FKHR, and 46 had neither translocation. One or the other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis showed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. The authors suggested that with the difficulties in morphologic diagnosis of alveolar rhabdomyosarcoma on small needle biopsy specimens, the molecular data may be useful in treatment stratification.

Sharp et al. (2002) showed that simultaneous loss of Ink4a/Arf (600160) function and disruption of Met (164860) signaling in Ink4a/Arf -/- mice transgenic for hepatocyte growth factor/scatter factor (Hgf/Sf; 142409) induces rhabdomyosarcoma with extremely high penetrance and short latency. In cultured myoblasts, Met activation and Ink4a/Arf loss suppressed myogenesis in an additive fashion. Sharp et al. (2002) concluded that human MET and INK4A/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in rhabdomyosarcoma pathogenesis. The marked synergism in mice between aberrant MET signaling and INK4A/ARF inactivation, lesions individually implicated in human rhabdomyosarcoma, suggested a therapeutic combination to combat this devastating childhood cancer.

Waardenburg syndrome, type I

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193500

1. 193500 GeneTests, Links

WAARDENBURG SYNDROME, TYPE I; WS1 Gene map locus 2q35 TEXT

A number sign (#) is used with the entry because Waardenburg syndrome type I is caused by mutation in the PAX3 gene (606597).

DESCRIPTION

The features of Waardenburg syndrome are wide bridge of the nose owing to lateral displacement of the inner canthus of each eye, pigmentary disturbance (frontal white blaze of hair, heterochromia iridis, white eye lashes, leukoderma), and cochlear deafness. The severity varies widely and some affected persons escape deafness.

NOMENCLATURE

WS type I (WS1) is distinguished from WS type II (WS2) by the presence in WS1 of dystopia canthorum, a lateral displacement of the inner canthi.

Klein's name is sometimes combined with Waardenburg's in the eponymic designation of this disorder, on the basis of a patient that Klein (1950) described with 'partial albinism,' blue eyes, deaf-mutism, undeveloped muscles and fused joints in the arms, skeletal dysplasia, etc. See 148820 for evidence that the Klein-Waardenburg syndrome, also known as Waardenburg syndrome type III, is due to an allelic mutation in the PAX3 gene or is a contiguous gene syndrome due to deletion of the PAX3 gene and adjacent genes.

CLINICAL FEATURES

Yoshino et al. (1986) evaluated the incidence of dystopia canthorum in a 3-generation family with Waardenburg syndrome and concluded that it is the most frequently expressed sign of the condition. Laestadius et al. (1969) provided normal standards for the measurement of inner canthal and outer canthal distance. Standards were also presented by Christian et al. (1969). Lateral displacement of the inner canthi is seen also in the oral-facial-digital syndrome type I (311200). Skipped generations and the occurrence of bilateral cleft lip were documented by Giacoia and Klein (1969)

Winship and Beighton (1992) reviewed phenotypic variation on the basis of an analysis of 68 affected children.

In a craniofacial anthropometric study of 51 WS type I individuals, da-Silva et al. (1993) concluded that the most discriminating parameters were, from clinical measurements, intercanthal distance (which was increased) and philtrum length (which was decreased) and, from roentgenographic measurements, nasal bone length (which was decreased) and lower facial height (which was increased). In place of the measurement of inner canthal distance, the Waardenburg Consortium (Farrer et al., 1992) recommended the W index: a composite measure including the inner canthal, inner pupillary, and outer canthal distances. Normal and dystopic subjects had W values (mean +/- S.D.) of 1.76 +/- 0.16 and 2.61 +/- 0.19, respectively (Newton, 1989); the Waardenburg Consortium recommended a threshold W value of 2.07. Individual I-2 had a W index of 2.21 but was the only member of the family with a value over 2.07. See 193510 for further discussion of type II Waardenburg syndrome which in some families is not linked to PAX3.

The disorder has been described in American blacks (Hansen et al., 1965) and in Maoris (Houghton, 1964) as well as in Europeans. Cleft palate and/or lip occurs in some cases. Premature graying of the hair is an effect of the gene. The fundus may be completely or partially albinotic and depigmented areas of skin like those of piebald trait (172800) may be present. In the state of South Australia, the Waardenburg syndrome is a leading cause of deafness and 'enjoys' a position comparable to porphyria in South Africa, having been introduced by early settlers who have many descendants (Fraser, 1967). The white forelock may be present at birth and later disappear (Feingold et al., 1967). Arias (1971) observed black forelock in place of white forelock. An affected Chinese family was reported by Chew et al. (1968).

Goodman et al. (1988) observed absence of vagina and of right-sided uterine adnexa in an 18-year-old woman with WS1. They postulated that these are related to Waardenburg syndrome because of altered invasion of neurons in early embryogenesis.

The occurrence of Hirschsprung disease (aganglionic megacolon; 142623) in patients with the Waardenburg syndrome is noteworthy (McKusick, 1973; Lowry, 1975; Omenn and McKusick, 1979). Fraser (1976) described a deaf male with no family history of deafness, complete blue-green heterochromia with hypoplastic stroma in the blue iris, and Hirschsprung disease. Chatkupt et al. (1993) stated that spina bifida had been noted in at least 4 patients with Waardenburg syndrome. Chatkupt et al. (1993) reported the cases of brothers with both Waardenburg syndrome and lumbosacral myelomeningocele. The mother had features of Waardenburg syndrome. Spina bifida occurs with the 'Splotch' mutation, which molecular studies indicate is the homologous disorder in the mouse.

Read and Newton (1997) provided a review of the clinical features and molecular basis of Waardenburg syndrome and other auditory pigmentary syndromes.

Pardono et al. (2003) studied 59 patients with Waardenburg syndrome from 37 families (30 with type I, 21 with type II, and 8 isolated individuals without telecanthus). All patients were examined for the presence of 8 cardinal diagnostic signs: telecanthus, synophrys, iris pigmentation disturbances, partial hair albinism, hearing impairment, hypopigmented skin spots, nasal root hyperplasia, and lower lachrimal dystopia. Using their own data as well as those collected from the literature, the authors estimated the frequencies of the cardinal signs of Waardenburg syndrome based on a sample of 461 affected individuals with type I and 121 with type II.

INHERITANCE

Jones et al. (1975) found evidence of paternal age effect in new mutations for this autosomal dominant disorder.

Kapur and Karam (1991) described a family in which 3 children with this disorder were born to normal, unrelated parents. Germline mosaicism was postulated.

According to the report of Zlotogora et al. (1995), the homozygous form of Waardenburg syndrome is a very severe disorder that has been called WS type III (148820). In a large kindred, including many individuals affected with Waardenburg syndrome type I, they found a child with a very severe form of type III. The child presented with dystopia canthorum, partial albinism, and very severe upper-limb defects. His parents were first cousins, and both were affected with a mild form of WS1. Molecular analysis showed homozygosity for a point mutation in the PAX3 gene (606597.0009). Since all homozygous PAX3 mutations in mice lead to severe neural tube defects and intrauterine or neonatal death, the survival of the homozygote in this case and the absence of neural tube defects were unexpected. Ayme and Philip (1995) indeed observed exencephaly in a fetus with possible homozygous Waardenburg syndrome. The fetus was the product of a mating between a gypsy brother and sister, both of whom had Waardenburg syndrome.

As noted later, dystopia canthorum, as measured by the W-index, is one of the key diagnostic features of WS1. Reynolds et al. (1996) sought to determine whether the W-index is influenced primarily by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. They studied both WS1-affected individuals and their WS1 unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations were consistent with additional (possibly polygenic) affects. Separate analyses of WS1-affected and WS1-unaffected individuals suggested that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influenced variation in dystopia canthorum. Reynolds et al. (1996) suggested that their approach should be applicable for assessing the 'genetic architecture' of variation associated with other genetic diseases.

While mutations in PAX3 seem to be responsible for most, if not all, WS1 cases, it is not clear what accounts for the reduced penetrance of deafness. Stochastic events during development may be the factors that determine whether a person with a PAX3 mutation will be congenitally deaf or not. Alternatively, genetic background, nonrandom environmental factors, or both may be significant. Morell et al. (1997) compared the likelihood for deafness in affected subjects from 24 families with PAX3 mutations and in 7 of the families originally described by Waardenburg. They found evidence that stochastic variation alone does not explain the differences in penetrance of deafness among WS families. Their analyses suggested that genetic background in combination with certain PAX3 alleles may be important factors in the etiology of deafness in WS1.

MAPPING

Simpson et al. (1974) and Arias et al. (1975) found a weak suggestion of linkage to the ABO locus, known to be located in 9q34. Read et al. (1989) excluded linkage to ABO. In a study of 2 large kindreds in northeastern Brazil, da-Silva et al. (1990) could not confirm linkage to ABO. Other studies of the same 2 Brazilian kindreds were reported by da-Silva (1991).

Since a plausible mouse model is 'Steel' (Sl), a dominant mutation on mouse chromosome 10 closely linked to Pep-2, Read et al. (1989) studied polymorphic probes for loci on human chromosome 12 close to PEPB, the human homolog, in 7 families. They excluded a sizable region of 12q as the site of this gene.

Ishikiriyama et al. (1989) reported the case of a 20-month-old boy with dystopia canthorum, sensorineural deafness, heterochromia iridis, partially albinotic ocular fundi, and partial leukoderma. Cytogenetic studies showed a paracentric inversion (2)(q35q37.3); his parents had normal chromosomes. Ishikiriyama et al. (1989) suggested that the gene for Waardenburg syndrome type I may be located at 2q35 or 2q37.3. Kirkpatrick et al. (1992) described WS type I in a child with del(2)(q35q36.2). Because of this report and that of Lin et al. (1992) of deletion of 2q37 without features of WS1, Ishikiriyama (1993) concluded that the WS1 gene is located at 2q35.

On the basis of an analysis of mouse and hamster mutants as models for Waardenburg syndrome(s), Asher and Friedman (1990) predicted that the gene(s) would be found to be on chromosome 2q near fibronectin-1, on chromosome 3p near the protooncogene RAF1 or 3q near rhodopsin, or on chromosome 4p near the protooncogene KIT. Foy et al. (1990) demonstrated linkage of the Waardenburg syndrome to placental alkaline phosphatase (ALPP; 171800), which had previously been assigned to 2q37; the peak lod score was 4.76 at a recombination fraction of 0.023. These findings suggest that the distal breakpoint responsible for the paracentric inversion is at the site of the Waardenburg syndrome, namely, 2q37.3. This region of chromosome 2 is homologous to mouse chromosome 1, which contains the 'Splotch' locus (Sp). This patchy pigment mutation is accompanied by a malformation of the inner ear and severe CNS malformation in the homozygote. Whether the heterozygote is deaf is unclear.

By PCR analysis of somatic cell hybrids, Pilz et al. (1993) mapped the PAX3 gene to chromosome 2.

Quoting William Harvey's famous observation that 'Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path,' Duyk et al. (1992) reviewed the forms of deafness, syndromal and nonsyndromal, for which linkage has been established.

Work in the hamster model for Waardenburg syndrome suggested to Asher and Friedman (1990) that modifier genes may account for the intrafamilial variation in phenotype in Waardenburg syndrome. In a family with 11 affected individuals spanning 4 generations, Asher et al. (1991) confirmed the assignment of WS1 to 2q. No recombination was found with ALPP at 2q37 or with FN1 (135600) at 2q34-q36. In a report from a consortium, Grundfast et al. (1991) concluded that only about 56% of WS families are linked to 2q markers. Furthermore, in the families with apparent linkage, they found no obligatory crossovers between WS1 and ALPP. For the whole collection of families, they obtained a maximum lod of 12.5 at theta = 0.31 for the WS1/ALPP linkage. Farrer et al. (1992) estimated that the WS1 gene on chromosome 2 was responsible for approximately 45% of the 44 families in their sample. Wilcox et al. (1992) used the intron between exons 2 and 3, amplified by PCR, as a probe to determine that the PAX3 gene is located on chromosome 2, from the study of DNA from somatic cell hybrids. They also identified a highly informative CA dinucleotide repeat.

Farrer et al. (1994) found that all families with WS1 showed linkage to the PAX3 region of chromosome 2. Three forms of WS2 (defined as absence of dystopia canthorum, i.e., W index less than 2.07) have been defined on the basis of linkage studies: WS2A (193510) due to mutation in the MITF gene (156845) maps to 3p; WS2B (600193) maps to 1p; and WS2C (606662) maps to 8p.

GENOTYPE/PHENOTYPE CORRELATIONS

In a series of patients with Waardenburg syndrome, Tassabehji et al. (1994) found a number of previously unidentified PAX3 mutations. These included a chromosomal deletion, a splice site mutation, and an amino acid substitution that closely corresponded to the molecular changes seen in the 'Splotch-retarded' and 'Splotch-delayed' mouse mutants, respectively. These mutations confirmed that Waardenburg syndrome is produced by gene dosage effects and showed that the phenotypic differences between 'Splotch' mice and humans with Waardenburg syndrome are caused by differences in genetic background rather than different primary effects of the mutations.

Chalepakis et al. (1994) studied the functional consequence of the mutations described in 606597.0001 and 606597.0006 on DNA binding and compared the results with those in the 'Splotch' mouse. Combining the phenotypic features of heterozygous mutants and considering that molecular defects ranging from single point mutations to large deletions cause similar phenotypes, they excluded the possibility that the mutated allele in heterozygotes interferes with the function of the wildtype allele. Contrariwise, they considered both WS and 'Splotch' mutants to represent loss-of-function mutations.

Baldwin et al. (1995) stated that their analysis of a total of 30 PAX3 mutations causing WS type I or type III demonstrated little correlation between genotype and phenotype. Deletions of the entire PAX3 gene resulted in phenotypes indistinguishable from those associated with single-base substitutions in the paired domain or homeodomain of the gene. Moreover, 2 similar mutations in close proximity could result in significantly different phenotypes, WS type I in 1 family and WS type III in another.

DeStefano et al. (1998) assessed the relationship between phenotype and gene defect in 48 families containing 271 individuals with WS collected by members of the Waardenburg Consortium. They grouped the 42 unique mutations previously identified in the PAX3 gene in these families into 5 mutation categories: amino acid substitution in the paired domain, amino acid substitution in the homeodomain, deletion of the ser-thr-pro-rich region, deletion of the homeodomain and the ser-thr-pro-rich region, and deletion of the entire gene. This classification of mutations was based on the structure of the PAX3 gene and was chosen to group mutations predicted to have similar defects in the gene product. They found that odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the pro-ser-thr-rich region compared to individuals with an amino acid substitution in the homeodomain. Odds ratios that differed significantly from 1.0 for these traits may indicate that the gene products resulting from different classes of mutations act differently in the expression of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for amino acid substitution in the paired domain compared with amino acid substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.

PATHOGENESIS

Mutations in MITF (156845) and PAX3, encoding transcriptions factors, are responsible for Waardenburg syndrome type II (193510) and WS1/WS3, respectively. Tachibana et al. (1996) showed that MITF transactivates the gene for tyrosinase (see 606933), a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair, and eyes, and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in WS2 are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations.

Watanabe et al. (1998) showed that PAX3 transactivates the MITF promoter. They further showed that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain failed the recognize and transactivate the MITF promoter. These results provided evidence that PAX3 directly regulates MITF, and suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1.

Bondurand et al. (2000) showed that SOX10 (602229), in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease.

Waardenburg syndrome, type III

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=148820

1. 148820 GeneTests, Links

WAARDENBURG SYNDROME, TYPE III; WS3 Alternative titles; symbols

KLEIN-WAARDENBURG SYNDROME WAARDENBURG SYNDROME WITH UPPER LIMB ANOMALIES WHITE FORELOCK WITH MALFORMATIONS

Gene map locus 2q35 TEXT

A number sign (#) is used with this entry because this disorder has been found to be caused by mutation in the PAX3 gene (606597). Both heterozygosity and homozygosity of mutations in the PAX3 gene had been observed in cases of type III Waardenburg syndrome.

Klein (1950) first reported the association of limb anomalies with what has come to be recognized as the hallmarks of the rather common Waardenburg syndrome (see 193500). Gorlin et al. (1976) considered the disorder with limb anomalies to be a separate entity (which might legitimately be referred to as the Klein-Waardenburg syndrome). Single cases were reported by Wilbrandt and Ammann (1964), Marx and Bertrand (1968), and Mossallam et al. (1974). Goodman et al. (1982) documented the combination of upper limb abnormalities and the facial and ocular abnormalities of the Waardenburg syndrome in a Yemenite Jewish brother and sister, and reviewed this association in 4 patients reported earlier. The bilateral upper limb anomalies included hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, and syndactyly. The brother, at age 23 years, had a head circumference of only 55 cm (height 161 cm), but presumably normal intelligence. The sister, at age 25 years, had marked microcephaly (head circumference 47 cm), severe mental retardation, and spastic paraplegia. Parental consanguinity was denied. Klein (1981) visited the patient of Marx and Bertrand (1968) and found that he had an 11-year-old son with classic facial changes of Waardenburg syndrome and winged scapulas but no gross or radiographic changes in the arms.

Goodman et al. (1980) reported the cases of 2 Ashkenazi Jewish brothers with a 'new' syndrome of white forelock (poliosis), distinctive facial features and congenital malformations of the ocular, cardiopulmonary and skeletal systems. Ocular hypertelorism, atrial septal defect, prominent thoracic and abdominal veins, hypoplastic or absent terminal phalanges of toes, and segmental bronchomalacia with atelectasis were features.

Goodman et al. (1982) favored autosomal dominant inheritance. The report by Sheffer and Zlotogora (1992) appeared to confirm autosomal dominant inheritance. They described in detail a brother and sister with dystopia canthorum, blepharophimosis, and bilateral flexion contractures of the fingers. The father and his sister, who had previously been reported by Goodman et al. (1982), showed the same features as described above. The flexion contractures in both the proposita and her father were pictured by Sheffer and Zlotogora (1992). Hoth et al. (1993) demonstrated a histidine for asparagine substitution (606597.0011) in the paired domain of the PAX3 gene in affected members of the family studied by Goodman et al. (1982) and Sheffer and Zlotogora (1992).

Milunsky et al. (1992) identified a mutation in the 'WS I gene' in a Yemenite/Russian Jewish family with the Klein-Waardenburg syndrome. The father, his 2 children, and his sister, but neither of his parents had signs of the Klein-Waardenburg syndrome. They were found to have an asn (AAC)-to-his (CAC) change in exon 2 of the PAX3 gene. In a sporadic case of type III Waardenburg syndrome with characteristic features of severe neurosensory deafness, diagnostic dysmorphic facial features, hypopigmentation, and severe axial and limb skeletal anomalies, Pasteris et al. (1992) identified a de novo deletion of 2q35-q36. Chromosome 2 homologs could not be distinguished by bivariant fluorescent-activated chromosome sorting, suggesting that the deletion was less than 5% of the chromosome length, i.e., less than 12.5 megabases. Densitometric hybridization analyses showed that the patient was hemizygous for loci HuP2 (PAX3) and COL4A3 (120070) and that flanking loci INHA (147380) and ALPI (171740) were present in 2 copies. Analyses of somatic cell hybrids selectively retaining the chromosome 2 showed that the deletion was paternal in origin. Physical mapping confirmed the deletion of 2q35-q36 and showed that COL4A3 is telomeric to PAX3. From these studies, Pasteris et al. (1992) concluded that type III Waardenburg syndrome is a contiguous gene syndrome. By molecular analysis of a chromosome 2 deletion mapping panel, Pasteris et al. (1993) determined that the order of loci on 2q is as follows: cen--(INHA, DES)--PAX3--COL4A3--(ALPI, CHRND)--tel. They also studied a patient with cleft palate and lip pits who lacked diagnostic WS features and found that the del(2)(q33q35) deletion involved the PAX3 locus. The finding suggested that not all PAX3 mutations are associated with a WS phenotype and that additional loci in the region may modify or regulate the PAX3 locus and/or the development of the WS phenotype.

Zlotogora et al. (1995) presented evidence that homozygosity for a PAX3 mutation can cause WS type III. In a large kindred, including many individuals affected with WS type I, a child was born affected with a very severe form of WS type III. The child presented with dystopia canthorum, partial albinism, and very severe upper-limb defects. His parents were first cousins and both were affected with a mild form of WS1. Molecular analysis of PAX3, the gene that was determined by linkage to cause the disorder in the family, demonstrated a novel missense mutation (S84F; 606497.0009) in exon 2 of PAX3 within the paired box. Individuals with WS1 were heterozygous for the mutation and the child with WS3 was homozygous. The observation that the PAX3 homozygote survived at least into early infancy and did not suffer from a neural tube defect was unexpected, since, in all the Pax3 mutations known in the mice, homozygosity leads to severe neural tube defects and intrauterine or neonatal death. Ayme and Philip (1995) likewise described possible homozygosity for a PAX3 mutation in a fetus with exencephaly and severe contractures and webbing of the limbs.

In their Figure 2, Tassabehji et al. (1995) pictured the hands of a man noted to have flexion contractures of the fingers characteristic of type III WS. A nonsense mutation with predicted truncation of the PAX3 gene product was found: deletion of a cytosine at nucleotide 916 in exon 6 in the homeodomain. The daughter, who was also pictured, and the mother of the proband were said to have type I WS.

Wollnik et al. (2003) reported a family in which both parents were heterozygous for a Y90H mutation in PAX3 (606597.0013)and had type I Waardenburg syndrome; the offspring was homozygous for the mutation and had type III Waardenburg syndrome.

ANIMAL MODEL

Homozygosity in the 'splotch' mouse, a mouse model for Waardenburg syndrome due to a PAX3 deletion, leads to neural tube defect in addition to severe limb defects Epstein et al. (1991).

SEE ALSO

Klein (1983)

Pax3 paired box gene 3 [ Rattus norvegicus ]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=114502

paired box gene 3

homeodomain protein PAX3

may act as a transcription factor and play a role in Schwann cell development; may be regulated by transcriptional modulator Sox10 [RGD]

1: Pax3 paired box gene 3 [ Mus musculus ]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=18505

Sp; Pax-3; splotch

Phenotypic Alleles: http://www.informatics.jax.org/searches/allele_report.cgi?markerID=MGI:97487

• oft weiße füße, Fleck auf dem Bauch, Knick im Schwanz, offenes Neuralrohr, neural crest: Neuralwülste, verschiedene Fehlbildungen und Verlagerung der Hauptarterrien

Pax3 paired-box 3 [ Xenopus laevis ]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=496376

Also known as Pax3; MGC131061

http://www.informatics.jax.org/searches/accession_report.cgi?id=MGI:97487

Mutations vary in severity, causing embryonic to perinatal death, malformation of neural tube, spinal ganglia, heart, vertebral column, hindbrain and limb musculature. Heterozygotes have white belly spots and variable spotting on the back and extremeties.

http://www.informatics.jax.org/searches/allele_report.cgi?_Marker_key=12181

• Waardenburg Syndrome, Type I; WS1 193500
• Waardenburg Syndrome, Type III; WS3 148820

lethality/embryonic-perinatal, cardiovascular, endocrine/exocrine, immune, nervous system, craniofacial, embryogenesis, hematopoietic, pigmentation, skin/coat/nails

growth/size, skin/coat/nails, limbs/digits/tail, pigmentation

muscle, skeleton

http://www.springerlink.com/content/t6732108h42t1454/

Einseitige Innenohrschwerhörigkeit bei Mutationen im PAX3-Gen bei Waardenburg-Syndrom Typ I Unilateral sensineural deafness associated with mutations in the PAX3-gene in Waardenburg syndrome type I Zeitschrift HNO Verlag Springer Berlin / Heidelberg ISSN 0017-6192 (Print) 1433-0458 (Online) Fachgebiet Medizin Heft Volume 54, Number 7 / Juli 2006 Kategorie Kasuistiken DOI 10.1007/s00106-005-1315-1 Seiten 557-560 SpringerLink Date Mittwoch, 14. September 2005

Zusammenfassung Das Waardenburg-Syndrom Typ I (WS-I) tritt infolge von Mutationen im sog. PAX3-Gen auf, das auf dem langen Arm des Chromosoms 2 lokalisiert wurde. Es wird autosomal-dominant mit sehr variabler Expressivität und hoher Penetranz vererbt. Die Symptomatik des WS-I ist bedingt durch das Fehlen von Melanozyten in der Haut, im Haar, in den Augen und in der Kochlea infolge einer Bildungsstörung der Melanozyten aus der Neuralleiste in der frühen Embryonalentwicklung. Typischerweise entsteht hierdurch auch eine Innenohrschwerhörigkeit. Im vorliegenden Fall wird über ein Kind mit einer einseitigen Surditas, einem deutlichen Telekanthus, einer Pigmentierungsstörung zwischen den Fingergrundgelenken der rechten Hand und im Bereich des Oberbauches sowie einer Heterochromie der Iris berichtet. Die molekulargenetische Diagnostik zeigte die Mutationen C64A und T164A im Exon I und II des PAX3-Gens. Beide Mutationen wurden bisher nicht beschrieben.

MITF

1. Mitf is conserved in Drosophila and functions in eye development

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=3885647

1: Mitf microphthalmia-associated transcription factor [ Mus musculus ]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4286

Mitf -/- : mouse with depigmentation, small eyes

This gene encodes a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. It regulates the differentiation and development of melanocytes retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified.

• Data show that MITF appears to regulate the expression of the SILV and MLANA genes.

Phenotypic Alleles

http://www.informatics.jax.org/searches/allele_report.cgi?markerID=MGI:104554

Mitf^Mi-b

• Homozygot: weiß, helle Augen
• Herozygot: Helle ohren, Heller Schwanz, aufgehellte Fellfarbe (braun)

Mitf^Mi-bcc2

• Homzygot: häufig Unfruchtbarkeit beider Geschlechter, weißes Fell, verkleinerte Augen, verringerter Erfolg beim säugen
• heterozygot: the dilute pigmented areas fade to light gray/white with age, while normally pigmented areas remain unchanged, white regions on the forehead, back and belly

Mitf^Mi-bw

• sowohl homozygot als auch heterozygot: mice are white with, infrequently, a few pigmented hairs on the back, Taubheit, stria vascularis was abnormally thin

Mitf^Mi-bws

• gescheckt, ansonsten gesund

Mitf^Mi-ce

• fahle augen, wolkig weiß, weiße Mäuse, abnormally thin or absent stria vascularis, average appearance of mating plug for paired matings is 13 days compared to 2 days for normal mice, females are unable to maintain a pregnancy when mated to a homozygous male: fetuses die between E16 and E18, manchmal Catarakt, asymmetrical eye opening (palpebral fissure) significantly smaller at all ages, eyes decrease in volume with age, cochlear hair cells not fully developed

Mitf^Mi-Crc

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=12819038

• Jinyan Du, Arlo J. Miller, Hans R. Widlund, Martin A. Horstmann, Sridhar Ramaswamy and David E. Fisher: MLANA/MART1 and SILV/PMEL17/GP100 Are Transcriptionally Regulated by MITF in Melanocytes and Melanoma

Silver

PMEL17 is the human homologue of murine silver, a locus whose disruption produces a significant pigmentation phenotype which resembles a silver color.21 Although the precise function of this gene (also known as GP100/SILV, hereafter referred to as SILV) remains to be ascertained, SILV localizes to an early melanosome trafficking compartment22 and may function in melanosome structure,23 biosynthesis of the melanin intermediate 5,6-dihydroxyindole-2-carboxylic acid (DHICA),24,25 or morphogenesis of premelanosomes.26

TIETZ SYNDROME

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=103500

1. 103500 Links

Alternative titles; symbols

ALBINISM-DEAFNESS OF TIETZ HYPOPIGMENTATION/DEAFNESS OF TIETZ TIETZ ALBINISM-DEAFNESS SYNDROME

Gene map locus 3p14.1-p12.3 TEXT

A number sign (#) is used with this entry because of evidence that Tietz syndrome is caused by mutation in the gene for microphthalmia-associated transcription factor (MITF; 156845).

Tietz (1963) described 14 persons in 6 generations with albinism and complete nerve deafness. The albinism was generalized but did not affect the eyes. The irides were blue. Nystagmus and other ocular abnormalities were absent. The medial canthi and nasal bridge were normal. The eyebrows were almost totally lacking. The albinism in this trait is hypopigmentation and not true albinism; the affected individuals tan, for example. Reed et al. (1967) thought this might have been merely a dominant type of deafness in unusually blond persons.

Smith et al. (2000) reascertained the family reported by Tietz (1963) and confirmed the existence of the syndrome through at least 4 generations. All affected individuals were born 'snow white,' but gradually gained some pigmentation, with fair skin and blond hair. Eyebrows and eyelashes remained blond. Eyes were blue with albinoid fundi, but no nystagmus or other visual problems were encountered. Craniofacial appearance was normal: specifically there was no dystopia canthorum. Hearing loss was always bilateral, congenital, and profound, and communication was primarily through signing. There was no variation in expression and penetrance was complete. Smith et al. (2000) demonstrated significant linkage to the region of the MITF gene and identified mutations in the MITF gene (156845.0006).

In a family with partial albinism and sensorineural deafness, Tassabehji et al. (1995) identified an in-frame 3-bp deletion in the MITF gene (delR217; 156845.0003). Amiel et al. (1998) presented detailed clinical findings on the affected mother and son and noted that although they fulfilled diagnostic criteria for Waardenburg syndrome type II (see 193510), they more closely resembled the family reported by Tietz (1963). Both mother and son had severe congenital sensorineural hearing loss. The mother had red hair as a child but underwent uniform premature graying at age 16 years, and had generalized hypopigmentation with numerous orange freckles. She had no dysmorphic features, and there was no dystopia canthorum. Her eyes were blue with no nystagmus or photophobia, and the irides did not transilluminate. The fundi in both patients were striking with lack of retinal pigmentation and enlarged, irregular optic disks.

WAARDENBURG SYNDROME, TYPE IIA; WS2A

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193510

1. 193510 GeneTests, Links

WAARDENBURG SYNDROME, TYPE IIA; WS2A Alternative titles; symbols

WS2

Gene map locus 3p14.1-p12.3 TEXT

A number sign (#) is used with this entry because one form of Waardenburg syndrome type II (WS2A) is caused by mutation in the gene encoding microphthalmia-associated transcription factor (MITF; 156845) on chromosome 3p. Another form, WS2D (608890), is caused by mutation in the SNAI2 gene (602150) on chromosome 8q11. Two other Waardenburg syndrome type II loci have been mapped: WS2B (600193) on chromosome 1p and WS2C (606662) on chromosome 8p23.

Arias (1971) suggested the existence of 2 types of Waardenburg syndrome. Hageman and Delleman (1977) presented family data supporting delineation of 2 types: type I, with dystopia canthorum; and type II, without dystopia canthorum. The frequency of deafness was higher in type II. Bard (1978) also described a kindred that was atypical in several ways. Although the nasal root was prominent, one affected person had dystopia of the inner canthi or lower puncta. The face in some showed striking freckling of pale skin. Symptomatic vestibular disturbance was another unusual feature. Lewis (1989) suggested that Bard's patients in fact had the disorder discussed in entry 103470. See later for evidence that digenic inheritance was responsible for the combination of type II Waardenburg syndrome and autosomal recessive ocular albinism in this kindred (Morell et al., 1997).

Arias (1980) suggested that visceral and cranial malformations (such as Hirschsprung megacolon) are associated with the type I form. Kelley and Zackai (1981) reported father and son with aganglionic megacolon and type II Waardenburg syndrome. Thus the suggestion that megacolon occurs only with type I Waardenburg syndrome may have no validity. Meire et al. (1987) also reported Hirschsprung megacolon with type II. The affected girl, 1 of 3 affected persons in her family, also showed unilateral ptosis with the Marcus Gunn phenomenon; the ptosis decreased on opening the mouth. In a patient with piebaldism and deafness, Kaplan and de Chaderevian (1988) found megacolon, left pulmonic artery stenosis, ocular ptosis, and unilateral duplication of the renal collecting system. Histologically, hypoganglionosis, hyperganglionosis, and ectopic ganglia were found in the lamina propria of the rectum (neuronal colonic dysplasia). The hypopigmented skin was found to be devoid of melanocytes, with no melanin in adjacent basal cells. Because of the absence of dystopia canthorum, the patient can be said to have had type II Waardenburg syndrome. (The name is spelled de Chadarevian in at least 4 other publications cited in Mendelian Inheritance in Man.)

Whereas classic Waardenburg syndrome (193500) has been proven to be due to mutations in the PAX3 gene (606597), a few type II families that have been studied have failed to show linkage to ALPP (171800) and/or PAX3 on 2q37 (Farrer et al., 1992; Tassabehji et al., 1993). See 193500.0006 for a description of a family in which a PAX3 mutation was found in association with a presumed WS2 phenotype.

In a study of 2 families with WS type II, Hughes et al. (1994) demonstrated linkage to a group of microsatellite markers located on 3p14.1-p12. D3S1261 gave a maximum lod score of 6.5 at 0.0 recombination in 1 large type II family. In a second, smaller family, the adjacent marker D3S1210 gave a lod score of 2.05 at 0.0 recombination. The human homolog of the mouse microphthalmia gene (MITF; 156845) maps to the same region. Asher and Friedman (1990) had pointed out that because of phenotypic similarities, microphthalmia (mi) is a possible model for Waardenburg syndrome; there are many mi alleles, some dominant and others recessive, which interact and complement in various ways, giving a range of phenotypes that can include white coat, premature graying, unpigmented eyes, and hearing loss. Tassabehji et al. (1994) demonstrated mutations in the MITF gene in patients with type II Waardenburg syndrome.

Not unexpectedly, Hughes et al. (1994) found that WS2 is heterogeneous, with mutations at different loci in different families. They suggested that the type II Waardenburg syndrome mapping to 3p13 be named WS2A and the unlinked form(s) provisionally designated WS2B. In a personally studied series of 81 individuals from 21 families with WS type II in comparison with 60 personally studied patients from 8 families with type I, Liu et al. (1995) concluded that sensorineural hearing loss (77%) and heterochromia iridum (47%) were more common in WS type II than in type I. On the other hand, white forelock and skin patches were more frequent in type I.

Reynolds et al. (1995) reviewed their collection of 26 WS1 and 8 WS2 families. Deafness was more frequent and more severe in the WS2-affected individuals than had been found previously. No one in either group had neural tube defects or cleft lip and/or palate. However, 12 individuals in 5 families had some signs or symptoms of Hirschsprung megacolon. Their data led Reynolds et al. (1995) to conclude that use of the W-index to discriminate between affected WS1 and WS2 individuals may be problematic since 1) ranges of W-index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2 families, and 2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum.

Several families have been reported in which Waardenburg syndrome type II and ocular albinism appear to cosegregate as a distinct genetic syndrome (WS2-OA; 103470). Morell et al. (1997) screened for MITF mutations in 1 of the WS2-OA families and discovered a 1-bp deletion in exon 8 of MITF (156845.0005). Furthermore, they found that all individuals with the OA phenotype were either homozygous or heterozygous for the R402Q mutation of the tyrosinase gene (203100.0009), a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity, and also heterozygous for the 1-bp deletion in MITF. Morell et al. (1997) proposed that the WS2-OA phenotype results from digenic interaction between a gene for a transcription factor, MITF, and a gene that it regulates, TYR. The family studied in this case was that originally reported by Bard (1978).

WAARDENBURG SYNDROME, TYPE II, WITH OCULAR ALBINISM, AUTOSOMAL RECESSIVE; WS2-OA

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=103470

1. 103470 Links

ALBINISM, OCULAR, WITH SENSORINEURAL DEAFNESS Alternative titles; symbols

WAARDENBURG SYNDROME, TYPE II, WITH OCULAR ALBINISM, AUTOSOMAL RECESSIVE; WS2-OA

Gene map locus 11q14-q21, 3p14.1-p12.3 TEXT

A number sign (#) is used with this entry because of evidence that the disorder may be the result of digenic inheritance of a mutation in the transcription factor gene MITF (156845.0005) and in a gene that it regulates, that for tyrosinase (TYR; 203100.0009).

Lewis (1978) found 7 affected males and 5 affected females in 3 consecutive generations of a Caucasian kindred. As in the X-linked Nettleship-Falls form of ocular albinism (300500) and in the autosomal recessive O'Donnell variety (203310), the patients showed reduced visual acuity, photophobia, nystagmus, translucent irides, strabismus, hypermetropic refractive errors, and albinotic fundus with foveal hypoplasia. The skin lesions showed macromelanosomes as in X-linked ocular albinism. Deafness, which was accompanied by vestibular hypofunction, lentigines even in unexposed areas, optic nerve dysplasia, and dominant inheritance distinguished this form of ocular albinism. (In the LEOPARD syndrome (151100) vestibular function is normal.) Lewis (1989) expressed the opinion that the family reported by Bard (1978) as an instance of Waardenburg syndrome in fact had this disorder. Lewis (1989) had also been told of 2 other small families with the syndrome. Goldberg (1966) described a Waardenburg syndrome family with apparent ocular albinism.

Morell et al. (1997) presented an update of the clinical findings in the family of Bard (1978). The deafness was sensorineural and congenital. Heterochromia iridis was a prominent feature in 1 sibship in which both segmental iris bicolor and complete heterochromia occurred. Most of the affected individuals showed transillumination defects of the iris. Hypopigmentation of the fundus was mild in some, moderate in others, and severe in yet others. Almost all affected individuals had strabismus and visual acuity defects. One individual with a prominent white forelock, characteristic of Waardenburg syndrome, was pictured.

Studying the family reported by Bard (1978), Morell et al. (1997) demonstrated apparent digenic inheritance resulting from a combination of heterozygosity for a 1-bp deletion in exon 8 of the MITF gene (156845.0005) and homozygosity or heterozygosity for the R402Q polymorphism of the tyrosinase gene (TYR; 203100.0009).

SOX10

http://www.genecards.org/cgi-bin/carddisp.pl?gene=SOX10

• Defects in SOX10 are a cause of Waardenburg syndrome type IV (WS4) [MIM:277580]; also

known as Waardenburg-Shah syndrome. WS4 is characterized by the association of Waardenburg features (depigmentation and deafness) and the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease)

• Defects in SOX10 are a cause of Yemenite deaf-blind hypopigmentation syndrome

[MIM:601706]. The disorder consists of cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma and severe hearing loss. Another case observed in a girl with similar skin symptoms and hearing loss but without microcornea or coloboma is reported as a mild form of this syndrome

• Defects in SOX10 are the cause of peripheral demyelinating neuropathy, central

dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) [MIM:609136]; also called neurologic variant of Waardenburg-Shah syndrome. PCWH is a rare, complex and more severe neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease

http://www.biologie.uni-erlangen.de/mibi/gradkoll/11wegner.htm

Transkriptionsfaktoren sind zentrale Steuerelemente zahlreicher Entwicklungsprozesse. So wurde in den letzten Jahren für Transkriptionsfaktoren der auf Metazoen beschränkten Sox-Genfamilie eine steuernde Funktion in so unterschiedlichen Prozessen wie Neurulation, Endoderm-Bildung, Hämatopoese und diversen Organogenesen aufgezeigt. Wir haben eine Beteiligung des Transkriptionsfaktors Sox10 an der Entwicklung zahlreicher Zelltypen aus den Zellen der Neuralleiste im Säuger nachgewiesen. Dazu gehören die Zellen des enterischen Nervensystems und die pigmentbildenden Melanozyten. Die Funktion von Sox10 lässt sich durch die direkte transkriptionelle Aktivierung von Zielgenen erklären, deren Genprodukte essentielle Funktionen in der Entwicklung dieser Zelltypen besitzen. Ein solches Gen ist das für eine Rezeptor-Tyrosinkinase kodierende c-ret im enterischen Nervensystem und das für einen Transkriptionsfaktor kodierende microphthalmia in Melanozyten.

Quelle

• Prof. Michael Wegner: Mechanistische Analyse der Interaktion zwischen den Transkriptionsfaktoren Sox10 und Pax3, Lehrstuhl für Biochemie und Pathobiochemie, Institut für Biochemie, Uni Erlangen http://www.biologie.uni-erlangen.de/mibi/gradkoll/11wegner.htm

http://www.opus.ub.uni-erlangen.de/opus/volltexte/2006/459/

Sox10 wird in der Neuralleiste und deren Derivaten exprimiert (Kuhlbrodt et al., 1998b) und ist kritisch für die Spezifizierung der Neuralleiste, der Entwicklung von Melanozyten und der terminalen Differenzierung von Oligodendrozyten. Es spielt eine Schlüsselrolle in der Entwicklung des peripheren und enterischen Nervensystems. Sox10Defekte verursachen Myelinisierungsstörungen, da es die Expression verschiedener Myelingene wie MBP oder P0 kontrolliert. Die Mutation beider Allele ist embryonal letal und durch schwere Defekte in verschiedenen Teilen des peripheren und enterischen Nervensystems charakterisiert. Heterozygote Mutationen wurden in Patienten mit Waardenburg-Shah-Syndrom entdeckt. Diese Krankheit kombiniert die klassischen Eigenschaften des Waardenburg-Syndroms (Taubheit Sox10 und Pigmentierungsstörungen) mit dem aganglionotischen Megacolon der Hirschsprung-Krankheit. Die spontane DOM (dominant megacolon)-Maus-Mutante stellt ein Modell für diese Krankheit dar, da hier ebenfalls Pigmentierungsdefekte und Megacolon auftreten. Als Zielgene von Sox10 wurden neben P0 und MBP c-ret, die Untereinheiten des nACh-Rezeptor ß4 und ?3, Connexin 32, Trp2, Mitf (microphthalmia transcription factor), Connexin 47, Cntf (ciliary neurotrophic factor) und Krox20 identifiziert, die Sox10 außer bei P0 zusammen mit Kofaktoren synergistisch aktiviert.

Quelle

• Sandra Wißmüller: Biochemische Analyse der Eigenschaften der HMG-Domäne des Transkriptionsfaktors Sox10. naturwissenschaftlichen Fakultäten der Friedrich-Alexander-Universität Erlangen-Nürnberg, 2006 http://www.opus.ub.uni-erlangen.de/opus/volltexte/2006/459/

c-Kit

Kit kit oncogene [ Mus musculus ]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=16590

Namen: c-kit. belly-spot, dominant spotting, spotted sterile male, Steel Factor Receptor, Dominant white spotting, c-kit proto-oncogene protein

http://www.informatics.jax.org/searches/allele_report.cgi?markerID=MGI:96677

Mutations at the Kit locus generally display phenotypic anomalies associated with gametogenesis, hematopoesis and melanogenesis. Mutations tend to be semidominant. Homozygotes or compounds of two different mutations are usually black-eyed white, sterile, and have severe macrocytic anemia, often causing death in utero or neonatally. Heterozygotes with wild-type have some white spotting with or without slightly diluted pigmentation; they are fertile, and they may be slightly anemic. The level of KIT kinase activity and the severity of phenotypic expression for each KitWallele correlates with the type of mutation. Mutations that abolish activity by deletion (e.g. KitW, KitW-19H) or point mutation (e.g. KitW-37J, KitW-42J) are homozygous lethal, while mutations with residual kinase activity (e.g. KitW-v, KitW-41J, KitW-57J) are homozygous viable.

• Kit^d18: Belly spot
• Kit^Ssm:
  • homozygot: die within 24 hours of birth, visually appear anemic at birth
  • heterozygot: variable body spotting: white spotting on belly, fore and hind limbs, and tail, male infertility: sterile on B10.M/Y genetic background; fertile on YT/Y,CBA/CaY,DBA/2JY, and A.CA/Y
• Kit^tm1.1Bsm:
• Kit:
• Kit:
• Kit:
• Kit:
• Kit:

cKITmelanom.pdf

c-kit ist eine transmembrane Rezeptor-Tyrosinkinase aus der Familie der PDGF (platelet-derived growth factor)- und CSF-1 (colony stimulating factor-1)Rezeptoren und ist beim malignen Melanom als Proto-Onkogen wirksam (Qiu et al., 1988; Yarden et al., 1987).

Die extrazelluläre Domäne von c-kit besteht aus fünf Immunglobulin-ähnlichen Regionen. Die ersten drei Regionen binden seinen Liganden SCF. Dies induziert eine Homodimerisierung des Rezeptors (Blechman et al., 1993b; Lev et al., 1993; Blechman et al., 1993a) und führt rasch zu einer erhöhten Autophosphorylierung des Rezeptors (Philo et al., 1996; Lev et al., 1992c; Lev et al., 1992b; Lev et al., 1992a; Lemmon et al., 1997; Blume-Jensen et al., 1991). Der c-kit-Rezeptor weist eine intrinsische Tyrosinkinaseaktivität auf (Majumder et al., 1988; Yarden et al., 1987).

Das c-kit-Protein wurde in diversen Zellen gefunden, wie etwa in Mastzellen und in Epithelzellen der Brustdrüse, der Speicheldrüse, der Schweißdrüsen sowie des Drüsengewebes der Speiseröhre. Disseminiert wurde das c-kit-Protein desweiteren im Interstitium von Testis und Ovarien gefunden, gruppiert in Teilen des zentralen Nervensystems wie Cerebellum, Hippocampus und Hinterhorn des Rückenmarks. Weiterhin wird der c-kit-Rezeptor in hämatopoetischen Stammzellen, in Mastzellen sowie in Keimzellen konstitutiv exprimiert (Galli et al., 1993a; Hamann et al., 1994; Strohmeyer et al., 1995).

In der Haut wurde c-kit in Melanozyten, vermehrt in denen der basalen Epidermis und der Haarfollikel, identifiziert (Lammie et al., 1994). Der c-kit-Rezeptor ist an der Proliferation, Adhäsion, Differenzierung, funktionellen Reifung sowie am Erhalt einer Vielzahl an differenzierten Zellen beteiligt (Alexander und Nicola, 1998; Kitamura et al., 1998; Ashman, 1999).

Weiterhin führen Defekte von c-kit zu Fehlfunktionen wie etwa Mastozytose und assoziierten hämatologischen Fehlfunktionen, die von myelodysplastischen bis hin zu myeloproliferativen Erkrankungen reichen. Zusätzlich entwickeln diese Patienten verstärkt myeloische Leukämien. Eine c-kit-Expression wurde desweiteren bei soliden Tumoren wie beispielsweise bei kleinzelligen Bronchialkarzinomen, gastrointestinalen Stromatumoren (GIST), Keimzelltumoren, Mammakarzinomen, Neuroblastomen, Ewing-Sarkomen, einigen Weichteilsarkomen sowie in papillären/follikulären Schilddrüsenkarzinomen nachgewiesen (Tsuura et al., 1994b; Hines et al., 1995a; Kindblom et al., 1998; Huizinga et al., 1995; Miettinen et al., 2000; Ricotti et al., 1998; Landuzzi et al., 2000).

Im Zusammenhang mit dem malignen Melanom haben mehrere Studien gezeigt, daß die Progression des malignen Melanoms mit dem Verlust der c-kit-ProtoOnkogen-Expression einher geht. So ist bei der Mehrzahl an metastatischen Läsionen und Melanomzellinien die Expression des c-kit-Rezeptors nicht nachweisbar (Lassam und Bickford, 1992; Natali et al., 1992; Zakut et al., 1993a). Der Expressionsverlust scheint aufzutreten, wenn die Zellen in die Dermis einwandern (Ohashi et al., 1996a). Umgekehrt führt bei Nacktmäusen die Transfektion des c-kit-Gens in metastatische Melanomzellen zur Inhibition des Tumorwachstums und des Metastasierungspotentials (Huang et al., 1996a).

Maus

Im Hinblick auf Melanozyten spielt der c-kit-Rezeptor bei der Differenzierung und zu einem geringeren Teil bei der Proliferation embryonaler Melanoblasten eine zentrale Rolle (Mayer und Green, 1968; MINTZ und RUSSELL, 1957). Das murine c-kit wurde auf dem White spotting (W)-Locus lokalisiert (Nocka et al., 1989; Chabot et al., 1988a; Geissler et al., 1988a).

Mensch

Vergleichbar dazu wurden beim Menschen Mutationen des c-kit-Rezeptors bei Patienten mit Piebaldismus identifiziert, einer Erkrankung, die mit der lokalen Reduktion der Melanozytenzahl einhergeht (Fleishman, 1996; Giebel und Spritz, 1991a). Dies läßt ebenfalls vermuten, daß c-kit für die Melanozytenentwicklung essentiell ist.

Quelle

• Olga Maksimovic: Untersuchungen zur Expression des c-kit-Rezeptors bei der Entstehung und Progression des malignen Melanoms. Inaugural-Dissertation zur Erlangung des Doktorgrades der Medizin, Universitätshautklinik Tübingen http://tobias-lib.ub.uni-tuebingen.de/volltexte/2006/2376/index.html

http://www.springerlink.com/content/tt7j1v5qhwjcpwxg/

Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor Zeitschrift Mammalian Genome Verlag Springer New York ISSN 0938-8990 (Print) 1432-1777 (Online) Fachgebiet Medizinund Biomedizin & Life Sciences Heft Volume 7, Number 11 / November 1996 DOI 10.1007/s003359900244 Seiten 822-830 SpringerLink Date Donnerstag, 19. Februar 2004 Beitrag markieren Add to shopping cart Zu gespeicherten Artikeln hinzufügen Request Permissions Diesen Artikel empfehlen

Autoren

M. Johansson Moller, R. Chaudhary, E. Hellmén, B. Höyheim, B. Chowdhary, L. Andersson Zusammenfassung

Abstract. Comparative mapping data suggested that the dominant white coat color in pigs may be due to a mutation in KIT which encodes the mast/stem cell growth factor receptor. We report here that dominant white pigs lack melanocytes in the skin, as would be anticipated for a KIT mutation. We found a complete association between the dominant white mutation and a duplication of the KIT gene, or part of it, in samples of unrelated pigs representing six different breeds. The duplication was revealed by single strand conformation polymorphism (SSCP) analysis and subsequent sequence analysis showing that white pigs transmitted two nonallelic KIT sequences. Quantitative Southern blot and quantitative PCR analysis, as well as fluorescence in situ hybridization (FISH) analysis, confirmed the presence of a gene duplication in white pigs. FISH analyses showed that KIT and the very closely linked gene encoding the platelet-derived growth factor receptor (PDGFRA) are both located on the short arm of Chromosome (Chr) 8 at band 8p12. The result revealed an extremely low rate of recombination in the centromeric region of this chromosome, since the closely linked (0.5 cM) serum albumin (ALB) locus has previously been in situ mapped to the long arm (8q12). Pig Chr 8 shares extensive conserved synteny with human Chr 4, but the gene order is rearranged.

Belt-Mutation Schweine

• Giuffra E, Evans G, Tornsten A, Wales R, Day A, Looft H, Plastow G, Andersson L: The Belt mutation in pigs is an allele at the Dominant white (I/KIT) locus. In: Mamm Genome. 1999 Dec;10(12):1132-6. PMID: 10594235

A white belt is a common coat color phenotype in pigs and is determined by a dominant allele (Be). Here we present the result of a genome scan performed using a Hampshire (Belt)/Pietrain (non-Belt) backcross segregating for the white belt trait. We demonstrate that Belt maps to the centromeric region of pig Chromosome (Chr) 8 harboring the Dominant white (I/KIT) locus. Complete cosegregation between Belt and a single nucleotide polymorphism in the KIT gene was observed. Another potential candidate gene, the endothelin receptor type A gene (EDNRA), was excluded as it was assigned to a different region (SSC8q21) by FISH analysis. We argue that Belt is a regulatory KIT mutation on the basis of comparative data on mouse KIT mutants and our previous sequence analysis of the KIT coding sequence from a Hampshire pig. Quantitative PCR analysis revealed that Belt is not associated with a KIT duplication, as is the case for the Patch and Dominant white alleles. Thus, Belt is a fourth allele at the Dominant white locus, and we suggest that it is denoted I(Be).

Kit Duplikation, roa

• Giuffra E, Tornsten A, Marklund S, Bongcam-Rudloff E, Chardon P, Kijas JM, Anderson SI, Archibald AL, Andersson L: A large duplication associated with dominant white color in pigs originated by homologous recombination between LINE elements flanking KIT. In: Mamm Genome. 2002 Oct;13(10):569-77. PMID: 12420135

The Dominant White (I/KIT) locus is one of the major coat color loci in the pig. Previous studies showed that the Dominant White (I) and Patch (IP) alleles are both associated with a duplication including the entire KIT coding sequence. We have now constructed a BAC contig spanning the three closely linked tyrosine kinase receptor genes PDGFRA-KIT-KDR. The size of the duplication was estimated at about 450 kb and includes KIT, but not PDGFRA and KDR. Sequence analysis revealed that the duplication arose by unequal homologous recombination between two LINE elements flanking KIT. The same unique duplication breakpoint was identified in animals carrying the I and IP alleles across breeds, implying that Dominant White and Patch alleles are descendants of a single duplication event. An unexpected finding was that Pietrain pigs carry the KIT duplication, since this breed was previously assumed to be wild type at this locus. Comparative sequence analysis indicated that the distinct phenotypic effect of the duplication occurs because the duplicated copy lacks some regulatory elements located more than 150 kb upstream of KIT exon 1 and necessary for normal KIT expression.

White spotting cat near KIT

• MP Cooper, N Fretwell, SJ Bailey, and LA Lyons: White spotting in the domestic cat (Felis catus) maps near KIT on feline chromosome B1. Anim Genet. 2006 April; 37(2): 163–165. doi: 10.1111/j.1365-2052.2005.01389.x.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16573531

Five feline-derived microsatellite markers were genotyped in a large pedigree of cats that segregates for ventral white spotting. Both KIT and EDNRB cause similar white spotting phenotypes in other species. Thus, three of the five microsatellite markers chosen were on feline chromosome B1 in close proximity to KIT; the other two markers were on feline chromosome A1 near EDNRB. Pairwise linkage analysis supported linkage of the white spotting with the three chromosome B1 markers but not with the two chromosome A1 markers. This study indicates that KIT, or another gene within the linked region, is a candidate for white spotting in cats. Platelet-derived growth factor alpha (PDGFRA) is also a strong candidate, assuming that the KIT–PDGFRA linkage group, which is conserved in many mammalian species, is also conserved in the cat.

(W) locus of the mouse

• Edwin N. Geissler, Melanie A. Ryan and David E. Housman: The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. In: Cell. Volume 55, Issue 1 , 7 October 1988, Pages 185-192, doi:10.1016/0092-8674(88)90020-7

Mutations at the W locus in the mouse have pleiotropic effects on embryonic development and hematopoiesis. The characteristic phenotype of mutants at this locus, which includes white coat color, sterility, and anemia, can be attributed to the failure of stem cell populations to migrate and/or proliferate effectively during development. Mapping experiments suggest that the c-kit proto-oncogene, which encodes a putative tyrosine kinase receptor, is a candidate for the W locus. We show here that the c-kit gene is disrupted in two spontaneous mutant W alleles, W44 and Wx. Genomic DNA that encodes amino acids 240 to 342 of the c-kit polypeptide is disrupted in W44; the region encoding amino acids 342 to 791 is disrupted in Wx. W44 homozygotes exhibit a marked reduction in levels of c-kit mRNA. These results strongly support the identification of c-kit as the gene product of the W locus.

Human Piebaldism

• Fleischman RA: Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene. In: J Clin Invest. 1992 Jun;89(6):1713-7. PMID: 1376329

Human piebald trait is an autosomal dominant defect in melanocyte development characterized by patches of hypopigmented skin and hair. Although the molecular basis of piebaldism has been unclear, a phenotypically similar "dominant spotting" of mice is caused by mutations in the murine c-kit protooncogene. In this regard, one piebald case with a point mutation and another with a deletion of c-kit have been reported, although a polymorphism or the involvement of a closely linked gene could not be excluded. To confirm the hypothesis that piebaldism results from mutations in the human gene, c-kit exons were amplified by polymerase chain reaction from the DNA of 10 affected subjects and screened for nucleotide changes by single-stranded conformation polymorphism analysis. In one subject with a variant single-stranded conformation polymorphism pattern for the first exon encoding the kinase domain, DNA sequencing demonstrated a missense mutation (Glu583----Lys). This mutation is identical to the mouse W37 mutation which abolishes autophosphorylation of the protein product and causes more extensive depigmentation than "null" mutations. In accord with this "dominant negative" effect, the identical mutation in this human kindred is associated with unusually extensive depigmentation. Thus, the finding of a piebald subject with a mutation that impairs receptor activity strongly implicates the c-kit gene in the molecular pathogenesis of this human developmental defect.

Sabinoscheckung beim Pferd

• Brooks SA, Bailey E: Exon skipping in the KIT gene causes a Sabino spotting pattern in horses. In: Mamm Genome. 2005 Nov;16(11):893-902. Epub 2005 Nov 11. PMID: 16284805

Sabino (SB) is a white spotting pattern in the horse characterized by white patches on the face, lower legs, or belly, and interspersed white hairs on the midsection. Based on comparable phenotypes in humans and pigs, the KIT gene was investigated as the origin of the Sabino phenotype. In this article we report the genetic basis of one type of Sabino spotting pattern in horses that we call Sabino 1, with the alleles represented by the symbols SB1 and sb1. Transcripts of KIT were characterized by reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing cDNA from horses with the genotypes SB1/SB1, SB1/sb1, and sb1/sb1. Horses with the Sabino 1 trait produced a splice variant of KIT that did not possess exon 17. Genomic DNA sequencing of KIT revealed a single nucleotide polymorphism (SNP) caused by a base substitution for T with A in intron 16, 1037 bases following exon 16. The SNP associated with SB1 was designated KI16+1037A. This substitution eliminated a MnlI restriction site and allowed the use of PCR-RFLP to characterize individuals for this base change. Complete linkage was observed between this SNP and Sabino 1 in the Tennessee Walking Horse families (LOD = 9.02 for Theta = 0). Individual horses from other breeds were also tested. All five horses homozygous for this SNP were white, and all 68 horses with one copy of this SNP either exhibited the Sabino 1 phenotype or were multipatterned. Some multipatterned individuals appeared white due to the additive effect of white spotting patterns. However, 13 horses with other Sabino-type patterns did not have this SNP. Based on these results we propose the following: (1) this SNP, found within intron 16, is responsible for skipping of exon 17 and the SB1 phenotype, (2) the White and Sabino phenotypes are heterogeneous and this mechanism is not the only way to produce the pattern described as "Sabino" or "White," and (3) homozygosity for SB1 results in a complete or nearly completely white phenotype.

Maus Kit

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15731517

• Hai-Bin Ruan, Nian Zhang and Xiang Gao: Identification of a Novel Point Mutation of Mouse Proto-Oncogene c-kit Through N-Ethyl-N-nitrosourea Mutagenesis. Genetics. 2005 Feb;169(2):819-31.

Manipulation of the mouse genome has emerged as an important approach for studying gene function and establishing human disease models. In this study, the mouse mutants were generated through N-ethyl-N-nitrosourea (ENU)-induced mutagenesis in C57BL/6J mice. The screening for dominant mutations yielded several mice with fur color abnormalities. One of them causes a phenotype similar to that shown by dominant-white spotting (W) allele mutants. This strain was named Wads because the homozygous mutant mice are white color, anemic, deaf, and sterile. The new mutation was mapped to 42 cM on chromosome five, where proto-oncogene c-kit resides. Sequence analysis of c-kit cDNA from Wadsm/m revealed a unique T-to-C transition mutation that resulted in Phe-to-Ser substitution at amino acid 856 within a highly conserved tyrosine kinase domain. Compared with other c-kit mutants, Wads may present a novel loss-of-function or hypomorphic mutation. In addition to the examination of adult phenotypes in hearing loss, anemia, and mast cell deficiency, we also detected some early developmental defects during germ cell differentiation in the testis and ovary of neonatal Wadsm/m mice. Therefore, the Wads mutant may serve as a new disease model of human piebaldism, anemia, deafness, sterility, and mast cell diseases.

Notitzen

• Linked markers exclude KIT as the gene responsible for appaloosa coat colour spotting patterns in horses. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11421946&query_hl=23&itool=pubmed_docsum
• Chinese White Rongchang Pig Does Not Have the Dominant White Allele of KIT but Has the Dominant Black Allele of MC1R. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17150979&query_hl=23&itool=pubmed_docsum
• Grahn RA, Lemesch BM, Millon LV, Matise T, Rogers QR, Morris JG, Fretwell N, Bailey SJ, Batt RM, Lyons LA:Localizing the X-linked orange colour phenotype using feline resource families. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15670134&query_hl=43&itool=pubmed_docsum