B4.3 MUTATIONS IN THE DESMOGLEIN 4 GENE UNDERLIE LOCALIZED AUTOSOMAL RECESSIVE HYPOTRICHOSIS IN HUMANS, RATS AND MICE

Amalia Martinez-Mir, ^*Celia Moss, ¹Ana Kljuic and Angela M. Christiano

Departments of Dermatology and Genetics & Development, Columbia University, New York, NY USA; ^*Department of Dermatology, Birmingham Children's Hospital NHS Trust, Birmingham, UK.

We recently defined a new form of inherited hair loss, named localized autosomal recessive hypotrichosis (LAH, OMIM 607903).  LAH is an autosomal recessive form of hypotrichosis affecting the scalp, trunk and extremities, and largely sparing the facial, pubic and axillary hair.  Typical hairs are fragile and break easily, leaving short sparse scalp hairs with a characteristic appearance. Genetic linkage studies were performed and established linkage to chromosome 18.  We then identified a large, intragenic deletion of exons 5-8 in the desmoglein 4 gene (DSG4) as the underlying mutation in two unrelated families of Pakistani origin. The in-frame deletion leads to an internally truncated protein missing amino acids 125-335.  These amino acids correspond to part of the EC1 domain, all of EC2 and the beginning of the EC3 domain.  These regions of DSG4 are believed to be critical in cadherin-cadherin interaction and dimerization necessary for proper cell-cell adhesion. Using comparative genomics, we also demonstrated that human LAH is allelic with the lanceolate hair (lah) mouse as well as the lanceolate hair (lah) rat phenotype. Recent reports of three additional Pakistani families with LAH-like features and linked to chromosome 18 also suggest that DSG4 mutations underlie the disease in these families.  We recently identified a LAH pedigree of Pakistani origin in the United Kingdom, and have identified the identical deletion in DSG4. Interestingly, the propagation of the identical mutation in Pakistani families throughout widespread geographic regions suggests that this allele represents an ancestral mutation that has been widely dispersed.  DSG4 is expressed in the inner epithelial layers of the hair follicle, where its function appears to be crucial during differentiation of the hair follicle layers. The significance of properly orchestrated adhesion during hair follicle development is underscored by several human disorders that result from mutations in adhesion plaque genes.