B4.1 HYPOTRICHOSIS SIMPLEX SIMPLEX OF THE SCALP IS CAUSED BY NONSENSE MUTATIONS IN THE CORNEODESMOSIN GENE

Elon Pras1, Etgar Levy-Nissenbaum, Regina C. Betz, Moshe Frydman, Michel Simon, Guy Serre, Markus M. Nöthen

1Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel

Hypotrichosis simplex of the scalp (HSS) is an autosomal dominant form of non-syndromic alopecia (MIM 146520), characterized by loss of scalp hair in late childhood or early adolescence. We have studied the molecular basis of this disorder in three unrelated HSS families, all of which showed linkage to chromosome 6p21.3. We have reduced the linkage interval to 9.5 Mb and embarked on a systematic study of all the genes from the interval, preferentially expressed in skin tissue. Nonsense mutations in the Corneodesmosin (CDSN) gene were identified in all three HSS families and the mutations were not observed in 750 unrelated control chromosomes. CDSN is a late differentiation epidermal glycoprotein thought to function as a keratinocyte adhesion molecule also expressed in the three epithelial components of the inner root sheet (IRS) of hair follicles. To study the consequences of the mutations we examined scalp biopsies from patients and controls using CDSN antibodies. In the patients, biopsies revealed reduced labelling intensity of the stratum granulosum in the epidermis and the IRS of hair follicles. The IRS in remaining follicles was strongly disturbed. Moreover, we noticed irregularly sized clusters located in ridges of the superficial dermis and at the periphery of hair follicles deeper in the dermis.

We have previously shown that a recombinant truncated form of CDSN is able to bind the entire CDSN, thus, a dominant negative interaction between the mutant and wild type protein may account for loss of cohesion within the IRS. However, in view of the delayed onset of alopecia and the fact that lost hair is not regenerated, it seems more likely that the observed CDSN aggregates are toxic to the hair follicle cells.  Our results underline a major role for CDSN in growth and maintenance of the scalp hair, and are an important step towards understanding the biological mechanisms underlying scalp-specific hair loss.