Mutation in Intron 6 of the Hamster Mitf Gene Leads to Skipping of the Subsequent Exon and Creates a Novel Animal Model for the Human Waardenburg Syndrome Type II

Corresponding author: Jochen Graw, Institute of Developmental Genetics, D-85764 Neuherberg, Germany., graw{at}gsf.de (E-mail)

Communicating editor: C. KOZAK

In the course of analysis of ENU-induced mutations in Syrian hamsters, a novel dominant anophthalmic white mutant (Wh^V203) with hearing loss was recovered. Because of this phenotype and a close linkage to the Tpi gene, the Mitf gene was considered as a candidate gene. In the Mitf cDNA, a deletion of 76 bp covering the entire exon 7 was detected. Further molecular analysis revealed a T A exchange 16 bp upstream of the end of intron 6, leading to skipping of exon 7. These 16 bp at the end of intron 6 are identical in hamster, rat, mouse, and humans, indicating high conservation during evolution and a functional importance in splicing. Since the loss of exon 7 changes the open reading frame of the MITF transcript, translation will be stopped after 10 new amino acids. The truncated protein is predicted to contain only a part of the basic region and will miss the two helical domains and the leucine zipper. The Wh^V203 mutation in the Syrian hamster affects the same functional domains of the Mitf transcription factor as the human R124X mutation, causing human Waardenburg syndrome type II. Therefore, the Wh^V203 hamster mutant provides a novel model for this particular syndrome.

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