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© 1992 Oxford University Press

RESEARCH-ARTICLE

A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family

Robert Morell1, Thomas B. Friedman1,2,3, Sukarti Moeljopawiro4,7, Hartono7,5, Soewito7,6 and James H. Asher, Jr.1,2,*

1Department of Zoology East Lansing, MI 48825-1115, USA 2Graduate Program in Genetics East Lansing, MI 48825-1115, USA 3College of Human Medicine, Michigan State University East Lansing, MI 48825-1115, USA 4Department of Biochemistry Yogyakarta, Indonesia 5Department of Ophthalmology Yogyakarta, Indonesia 6Department of Otolaryngology Yogyakarta, Indonesia 7Inter University Center for Biotechnology, Gadjah Mada University Yogyakarta, Indonesia

*To whom correspondence should be addressed

Received April 28, 1992; Revised June 8, 1992; Accepted June 8, 1992

Waardenburg syndrome type 1 (WS1) is an autosomal dominant disorder characterized by deafness, dystopia canthorum, heterochromia iridis, white forelock, and premature greying. A similar phenotype is caused in the mouse by mutations in the Pax-3 gene. This observation, together with comparisons of conserved syntenies in the murine and human genetic maps, suggested that at least some WS1 mutations should occur in HuP2, the probable human homolog of Pax-3. Two mutations in the HuP2 sequence of individuals with WS1 have been reported recently. Both of them occur in the highly conserved paired box region of the gene, which encodes a DNA binding domain. The functional consequences of these mutations are at present speculative. We report here a 14 bp deletion in the paired domain encoded by exon 2 of HuP2 in an Indonesian family segregating for WS1. This frameshift mutation results in a premature termination codon in exon 3. The HuP2 product is a truncated protein lacking most of the paired domain and all of the predicted homeo domain. We propose that the WS1 phenotype in this family is due to loss of function of HuP2 and discuss two mechanisms for the dominant effect of this mutation.


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