MUTATION AT THE ANOPHTHALMIC WHITE LOCUS IN SYRIAN-HAMSTERS - HAPLOINSUFFICIENCY IN THE MITF GENE MIMICS HUMAN WAARDENBURG-SYNDROME TYPE-2

Mutations in MITF (microphthalmia transcription factor) cause Waardenb urg syndrome type 2 (WS2A) in humans, an autosomal dominant disorder c onsisting of deafness and hypopigmentation. Phenotypes vary significan tly within WS2 pedigrees, and there is generally no correlation betwee n the predicted biochemical properties of mutant MITF proteins and dis ease severity, We have identified a nonsense mutation in the Mitf gene of the anophthalmic white (Wh) Syrian hamster that destabilizes its m RNA and prevents the encoded basic helix-loop-helix leucine zipper (bH LHzip) protein from dimerizing or binding DNA target sites, Although t he resulting polypeptide does not act as a dominant-negative species i n vitro, the Wh mutation is inherited as a semi-dominant trait, It thu s more closely resembles WS2 than comparable Mitf alleles in laborator y mice and rats, which are expressed as purely recessive traits.