Identification of mutations in the human hairless gene in two new families with congenital atrichia

Regina C. Betz, Margarita Indelman, Jana Pforr, Felix Schreiner, Ralf Bauer, Reuven Bergman, Michael J. Lentze, Markus M. Nöthen, Sven Cichon, Eli Sprecher

Congenital atrichia (AUC) is a form of isolated alopecia with an autosomal recessive mode of inheritance. Patients are born with normal hair but this is shed almost completely during the first weeks or months of life and never regrows. In many families the development of papular lesions is noted as an additional phenotypic feature, which defines a related phenotype designated as atrichia with papular lesions (APL). Using positional cloning strategies and the molecular findings in hairless recessive (hr/hr) mice, an animal model for AUC, mutations in the human hairless gene (HR) have been identified as a cause of AUC and APL. To date, more than 20 different mutations of the HR gene have been reported in AUC and APL including different mutation types scattered over the entire HR gene length. In this report, we describe two families of Saudi Arabian and Jewish Iranian origin comprising a number of individuals with clinical features suggestive of AUC. We therefore hypothesized that affected members may carry mutations in the HR gene. After sequencing the complete coding region of the HR gene in the Saudi Arabian family, we identified a homozygous insertion of a G (c.2661dupG; p.Thr888DfsX38) in exon 12, resulting in a premature stop codon. In a Jewish Iranian patient, we identified a homozygous splice site mutation c.1557-1G > T in intron 4. The latter mutation has been previously reported in a compound heterozygous state. In the present report, we describe the second exonic insertion mutation in the human HR gene and the first mutation in exon 12. Our study emphasizes the importance of sequencing the complete coding sequence and exon/intron junctions in the molecular diagnostics of AUC and APL.