F23 HUMAN NUDE-ITY EXPOSED: A NONSENSE MUTATION IN THE WHN GENE UNDERLIES CONGENITAL ALOPECIA AND NAIL DYSTROPHY WITH SEVERE T-CELLS IMMUNODEFICIENCY.

^1,2J. Frank, 3C. Pignata, ³L. Gaetaniello, ³N. Pozzi and ^4,5A. M. Cristiano; ¹Dept. of Dermatology and ²IZKF Aachen, University Clinic of the RWTH, Aachen, Germany; ³Dept. of Pediatrics, “Federico II” Universtiy, Naples, Italy; Depts. of ⁴Dermatology and ⁵Genetics and Development, Columbia University, New York, N.Y.

The murine nude phenotype results from mutations in the whn (winged-helix-nude) gene encoding a forkhead/winged helix transcription factor family member characterized by exclusive expression in thymus and skin. Phenotypically, these animals show congenital absence of hair and severe immunodeficiency. So far, identification of the human counterpart of the nude mutation has remained elusive. Recently however, the simultaneous occurrence of severe functional T-cell imunodeficiency, congenital alopecia and nail dystrophy (OMIM601705) in two female siblings of Italian ancestry was reported. One sibling survived due to a bone marrow transplantation which corrected the immunodeficiency, but not the congenital alopecia. To investigate if this syndrome represents a candidate disorder for underlying mutations in the human whn gene, we performed haplotype analyses and found suggestive evidence of linkage to the whn gene, we performed haplotype analyses and found suggestive evidence of linkage to the whn locus on human chromosome 17 (Zmax=1.32). Mutation analysis revealed a holozygous nonsense mutation in affected individuals, which was present in the heterozygous state in obligate carriers, and in many members of the extended family originating from the same village. Further, we localized the expression of human whn to specific tissues involved in the pathogenesis of the disorder. These findings demostrate the involvement of a forkhead/winged helix family member in the etiology of such diverse developmental defects as congenital absence of the hair and athymia in humans.