Identification of a genetic defect in the hairless gene in atrichia with papular lesions: evidence for phenotypic heterogeneity among inherited atrichias.

Recently, we showed that atrichia with papular lesions (APL), a rare inherited form of alopecia, is transmitted as an autosomal recessive trait in a large inbred kindred of Israeli-Arab origin. Furthermore, we mapped the APL locus to a 5-cM region of chromosome 8p12 in this family. The human "hairless" gene is a candidate target gene for the disease mutation because it maps to the APL locus and because it was recently found to be mutated in a related but clinically distinct form of alopecia known as "alopecia universalis" or "congenital alopecia." In the present study, the coding sequence of the hairless gene was compared by reverse transcription-PCR in fibroblast cell lines derived from an affected patient and an unrelated individual. We identified a single-base deletion (3434delC) in the hairless gene that cosegregated with the disease phenotype in the family. This deletion is predicted to cause a frameshift mutation in the highly conserved C-terminal part of the hairless protein, a region putatively involved in the transcription factor activity of the hairless gene product. The present results are indicative of phenotypic heterogeneity in inherited atrichias caused by mutations in the hairless gene, suggesting different roles for the regions mutated in APL and in other forms of congenital atrichia during hair development.