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Mouse and Hamster Mutants As Models for Waardenburg Syndromes in Humans

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Mouse and Hamster Mutants As Models for Waardenburg Syndromes in Humans J Med Genet: first published as 10.1136/jmg.27.10.618 on 1 October 1990. Downloaded from 6186J Med Genet 1990; 27: 618-626 Mouse and hamster mutants as models for Waardenburg syndromes in humans James H Asher Jr, Thomas B Friedman Abstract characteristics.2 Six of these characteristics form the Four different Waardenburg syndromes have been key to diagnosis: (1) dystopia canthorum, (2) a broad defined based upon observed phenotypes. These nasal root, (3) hypertrichosis of the medial ends of the syndromes are responsible for approximately 2% of eyebrows, (4) hypopigmentation of the skin and head subjects with profound congenital hearing loss. At hair, (5) total or partial heterochromia iridis, and present, Waardenburg syndromes have not been (6) congenital unilateral or bilateral deafness.6 Some mapped to particular human chromosomes. One or of the phenotypic effects caused by WS1 are illus- more of the mouse mutant alleles, Ph (patch), s trated by a 23 year old female who has significant (piebald), Sp (splotch), and Mior (microphthalmia- hearing loss and her 5 year old daughter who is Oak Ridge) and the hamster mutation Wh (anoph- profoundly deaf (fig la, b). thalmic white) may be homologous to mutations Premature graying of head hair and beard occurs in causing Waardenburg syndromes. In heterozygotes, approximately 33% of subjects with WS1,7 while phenotypic effects of these four mouse mutations optic abnormalities including iridial hypoplasia, and the hamster mutation are similar to the pheno- hypopigmentation of the fundus, coloboma, and types produced by different Waardenburg syndrome microphthalmia occur in approximately 51% of the mutations. The chromosomal locations and syn- cases reported.' 7 8-12 WS1 subjects may also exhibit copyright. tenic relationships associated with three of the cleft lip, cleft palate, or cleft face with a frequency of four mouse mutant genes have been used to predict up to 10%,7 13 4while cardiac abnormalities including human chromosomal locations for Waardenburg septal defects are occasionally observed.2 3 5-18 In syndromes: (1) on chromosome 2q near FN1 families where radiographical studies have been (fibronectin 1), (2) on chromosome 3p near the performed, high frequencies of minor skeletal abnor- proto-oncogene RAF1 or 3q near RHO (rhodopsin), malities are observed.' 1921 and (3) on chromosome 4p near the proto-oncogene In certain extended families, dystopia canthorum KIT. Waardenburg syndromes show extensive shows a penetrance of 98% and serves as a reliable http://jmg.bmj.com/ intrafamilial phenotypic variability. Results of our indicator of Waardenburg syndrome.' In these studies with the hamster mutation Wh suggest that families, penetrance of bilateral profound deafness in this variability may be explained in part by modifier heterozygotes was initially reported as 17%,' but with genes segregating within families. a larger data set this frequency is closer to 25%.22 The frequency of Waardenburg syndrome among students from schools for the deaf in the Netherlands and with an Classical Waardenburg syndrome in humans (WS1, Canada is 1-43% and 2-7%, respectively, on September 26, 2021 by guest. Protected MIM 19350) is caused by an autosomal dominant estimate of affected persons in the general population mutation with extensive phenotypic variation of 1/42 000 and a mutation rate of 1/270 000.1 23 The observed both within and between families. l-5 There WS1 mutation is a significant cause of congenital have been no reported cases of persons homozygous deafness and hearing impairment in humans. for WS1. In heterozygotes, the WS1 mutation is Observing the range ofphenotypes initially reported highly pleiotropic, affecting at least 18 different by Waardenburg,l investigators have defined four different subdivisions of Waardenburg syndromes. Arias,6 24 and later Hageman and Delleman,22 Department of Zoology and Graduate Program in suggested that patients with Waardenburg syndrome Genetics, 203 Natural Science Building, Michigan State but lacking dystopia canthorum should be classified University, East Lansing, Michigan 48824, USA. as Waardenburg syndrome type II (WS2, MIM J H Asher Jr, T B Friedman 19351). This syndrome is caused by an autosomal Correspondence to Dr Asher. dominant mutation. The frequency of profound bilateral deafness among heterozygotes for WS2 is approximately 50%,22 twice the frequency observed Received for publication 5 February 1990. Accepted for publication 27 March 1990. among WS1 heterozygotes. This subdivision of J Med Genet: first published as 10.1136/jmg.27.10.618 on 1 October 1990. Downloaded from Mouse and hamster mutants as models for Waardenburg syndromes in humans 619 copyright. http://jmg.bmj.com/ on September 26, 2021 by guest. Protected --Odlfw,. ',*. ANP,P--. A.b- .-I Figure 1 Two human subjects with Waardenburg syndrome (WSI) and mouse and hamster mutants showing similarphenotypes. (a) A 23year old woman with dystopia canthorum, broad nasal root, whiteforelock, isochromia iridis, and premature graying. She has aflat auditory brainstem evoked response (ABR) at 100 dB normal hearing level (nHL) in the right ear and has an ABR threshold of 45 dB nHL in the left ear while normal thresholds are 20 to 25 dB nHL. When not shaved, her eyebrows arefused. (b) The 5year old daughter ofthe subject tn (a). The daughter has dystopia canthorum, broad nasal root, fused eyebrows, whiteforelock, total heterochromia iridis, andprofound deafness. She has a 6 month old halfsister who givesflat ABR responses in both ears at 130 dB nHL. (c) A C3HflRl Mi'l+ mouse with a white head blaze, light ears, light eyes and a white belly patch. Homozygotes (Mi t/Mi0r) have a comoletelv white coat and are hrofoundlv deafand eveless. (d) A normal agouti Svrian hamster ofthe genotvoe whlwh:Ele. J Med Genet: first published as 10.1136/jmg.27.10.618 on 1 October 1990. Downloaded from 620 Asher, Friedman Waardenburg syndrome also contains patients with deletions involving 2q.42' So far, a causal con- ocular albinism.25 nection has not been established between this para- Waardenburg syndrome type III (WS3, MIM centric inversion and the WS1 phenotype. 14882, Klein-Waardenburg syndrome or Waarden- In a case involving a deletion of a nearby area, Glass burg syndrome with upper limb abnormalities) is a et aP47 described a 16 year old proband with cranio- third subdivision of patients initially considered by facial dysmorphology, extensive scalloped hypo- Waardenburg' as belonging to WS1. 6This mutation pigmentation of the skin, microcephaly, mental also behaves as an autosomal dominant. Hetero- retardation, no comprehensible speech, short stature, zygotes with this disorder have the classical WS1 beaked nose, bilateral corneal ectasia, divergent phenotype in addition to upper limb abnormalities, strabismus, bilateral ptosis, and cleft palate. The which include hypoplasia of the musculoskeletal hearing capabilities of this child were not reported. system and syndactyly. Some patients also exhibit The boy was heterozygous for an interstitial deletion microcephaly and severe mental retardation.26 27 involving 2q32.2-q33.1. Though not present in this Persons with a fourth subdivision of Waardenburg subject, skeletal abnormalities and coloboma were syndromes, designated as Waardenburg syndrome noted in subjects with deletions involving the same variant, Waardenburg-Shah syndrome, Shah- genetic region.4854 Hypopigmentation was not Waardenburg syndrome, or Hirschsprung disease observed in these latter deletions. We note that the with pigmentary anomaly (MIM 27758), exhibit many subject reported by Glass et at47 shares many of the of the classical WS1 characteristics in addition to features of Waardenburg syndrome type III. These having megacolon.2>32 This apparent variant of reports suggest the possibility that Waardenburg Waardenburg syndrome is caused by an autosomal syndrome mutations might map to human chromo- recessive mutation. Megacolon has also been found in some 2. association with the phenotypic effects of WSI and A genetic and developmental analysis of Waarden- WS2, but Waardenburg-Shah syndrome is considered burg syndromes will determine: (1) the number of distinct from the syndromes caused by these two genetic loci responsible for Waardenburg syndromes, mutations.5 (2) the number of mutant alleles at a given locus with The complex phenotypic variation observed both different phenotypic effects, (3) the primary functions copyright. within and between families with Waardenburg of the loci involved, and (4) the mechanisms by which syndromes may be explained by one of at least three alterations of these primary functions produce different genetic models: (1) a single locus with abnormalities of the eye, inner ear, pigmentation, and several mutant alleles, (2) a single locus with several skeleton. An obvious first step to obtain this informa- mutant alleles each interacting with modifying genes, tion is to assign WS 1 and WS2 to particular human and (3), as suggested by Waardenburg,' more than chromosomes using RFLP markers with known map one locus each with multiple mutant alleles which positions. To narrow the initial choice of autosomal http://jmg.bmj.com/ interact with modifying genes. Differences in the RFLP markers to be used in such a linkage analysis, allelic state of modifying genes are invoked to explain mutations in other mammals which may be homo- the variation observed both among and within logous to WS 1 and WS2 can be used to predict families with Waardenburg syndromes. possible
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