Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family

Waardenburg syndrome (WS) is an autosomal-dominant neural crest cell disord er phenotypically characterized by hearing impairment and disturbance of pi gmentation. A presence of dystopia canthorum is indicative of WS type 1, ca used by loss of function mutation in the PAX3 gene, In contrast, type 2 WS (WS2) is characterized by normally placed medial canthi and is genetically heterogeneous; mutations in MITF (microphthalmia associated transcription f actor) associated with WS2 have been identified in some but not all affecte d families. Here, we report on a three-generation Indian family with a poin t mutation in the MITF gene causing WS2, This mutation, initially reported in a Northern European family, creates a stop codon in exon 7 and is predic ted to result in a truncated protein lacking the HLH-Zip or Zip structure n ecessary for normal interaction with its target DNA motif. Comparison of th e phenotype between the two families demonstrates a significant difference in pigmentary disturbance of the eye. This family, with the first documente d case of two unrelated WS2 families harboring identical mutations, provide s additional evidence for the importance of genetic background on the clini cal phenotype, Am. J. Med. Genet. 80:406-409, 1998. (C) 1998 Wiley-Liss, In c.