title: Mutation at the anophthalmic white locus in Syrian hamsters: haploinsufficiency in the Mitf gene mimics human Waardenburg syndrome type 2.
abstract: Mutations in MITF (microphthalmia transcription factor) cause Waardenburg syndrome type 2 (WS2A) in humans, an autosomal dominant disorder consisting of deafness and hypopigmentation. Phenotypes vary significantly within WS2 pedigrees, and there is generally no correlation between the predicted biochemical properties of mutant MITF proteins and disease severity. We have identified a nonsense mutation in the Mitf gene of the anophthalmic white Wh) Syrian hamster that destabilizes its mRNA and prevents the encoded basic helix-loop-helix leucine zipper (bHLHzip) protein from dimerizing or binding DNA target sites. Although the resulting polypeptide does not act as a dominant-negative species in vitro , the Wh mutation is inherited as a semi-dominant trait. It thus more closely resembles WS2 than comparable Mitf alleles in laboratory mice and rats, which are expressed as purely recessive traits.
authors.affiliation: Howard Hughes Medical Institute, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0650, USA. chodg@mmg2.im.med.umich.edu
authors.forename: C A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: A
authors.initials: A
authors.lastname: Nakayama
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: L B
authors.initials: LB
authors.lastname: Swenson
authors.forename: K
authors.initials: K
authors.lastname: Opdecamp
authors.forename: J H
authors.initials: JH
authors.lastname: Asher
authors.forename: H
authors.initials: H
authors.lastname: Arnheiter
authors.forename: T
authors.initials: T
authors.lastname: Glaser
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000853:Anophthalmos / Q000235:genetics*; D015152:Blotting, Northern; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006238:Haploidy; D007150:Immunohistochemistry; D008647:Mesocricetus; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D009154:Mutation; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors