P-03   THE LANCEOLATE RAT PHENOTYPE IS CHARACTERIZED BY A DEFECT IN HAIR FOLLICLE KERATINIZATION AND RESULTS FROM A MUTATION IN THE DESMOGLEIN 4 GENE

CAB Jahoda, N. Crossley*, J. Whitehouse, M. Robinson, AJ Reynolds, RM Porter**, R. Suresh***, R. O’Shaugnessy***, A. Kljuic***, AM Christiano***. School of Biomedical and Biological Sciences, University of Durham, UK. *Department of Clinical Sciences, University of Leeds, UK. **Department of Anatomy and Physiology, University of Dundee, UK UK. ***Departments of Dermatology and Genetics & Development, Columbia University, New York, NY, USA.

Desmoglein 4 is a newly identified member of the desmosomal cadherin gene family in mammals. The gene was recently cloned in the mouse, rat and human genomes, and was shown to underlie both the lanceolate mouse phenotype (lah/lah), as well as the corresponding human disorder, localized autosomal recessive -32- hypotrichosis (LAH). LAH is characterized by a localized scalp-restricted hypotrichosis with sparse and fragile hair shafts. In mouse, the lah/lah phenotype was named due to the appearance of a lance head shaped defect in the keratinization of the hair shaft, and a profound defect in the precortical hair matrix cells was described. Here, we report identification of the rat counterpart of the lanceolate phenotype, designated lah/lah. Affected animals display hypotrichosis with fragile and broken hair shafts. Histological analysis revealed the presence of lance-head abnormalities on anagen hair shafts, as well as the presence of lance-tipped hairs emerging from the skin surface. Based on the genetic and phenotypic analysis of the lah rat, we cloned and sequenced the rat ortholog of the Dsg4 gene on rat chromosome 18, and identified a missense mutation in exon 6 of the gene that was not present in a group of unrelated, unaffected animals. This residue is highly conserved in the mouse and human genomes, suggesting that it is a functional mutation. Further, this mutation occurs in the second extracellular repeat region, immediately downstream of the missense mutation identified in the lah/lah mouse allele. Comparative histological analysis of the rat and mouse phenotypes support an integral role for dsg4 in the differentiation of hair follicle keratinocytes.