O#08   Advances in the molecular genetics of the hair follicle

M.A.M. van Steensel, M. van Geel, B.J.H. Jansen, R. Bladergroen, P.M. Steijlen
Dept of dermatology, UMC Nijmegen Sint Radboud, The Netherlands

The past year has seen several important and fundamental advances in our understanding of the molecular mechanisms governing hair follicle growth and differentiation. Among the most exciting is the finding that evolutionary pathways that determine the balance between life and death govern important aspects of epidermal appendage development. The gene mutated in X-linked hypohidrotic ectodermal dysplasia (XHED), ectodysplasin (EDA) has a receptor called EDAR. Mutations in the receptor gene cause an identical phenotype. The ligand belongs to the TNF superfamily and the receptor to the TNF receptor superfamily. The TNF superfamily molecules are involved in such diverse processes as immune regulation and apoptosis. The latter role suggested that it is important to tightly regulate apoptosis during development. The connection between the receptor and downstream mechanisms remained elusive. The EDA pathway signals through NfkB to stimulate cell survival. Interestingly, the NK-kB activator NEMO is involved in the pathogenesis of incontinentia pigmenti (IP). From a molecular genetics point of view, XHED is a cousin of IP. When looking at the phenotypes with this in mind, we see several similarities and conclude that both disorders are essentially disorders of apoptosis. On the other side of the scale, unchecked growth can also contribute to skin pathology. In keratitis-ichthyosis-deafness (KID) syndrome, erythrokeratoderma and deafness are cardinal symptoms. However, a congenital hypotrichosis and cancer-proneness are also part of the phenotype. We recently identified connexin 26 mutations in KID syndrome and were thus the first to show that gap junction proteins can act as tumor suppressors and regulators of growth in humans. This was known from animal studies but not predicted for humans. It is tempting to speculate that the unchecked cell growth reflected in the keratoderma and the cancer-proneneness of KID syndrome is also responsible for the hypotrichosis for instance by disturbing the carefully orchestrated pattern of cell death and growth in the hair follicle. Indeed, the hairless phenotype, caused by dysregulation of apoptosis, shows that unchecked hair follicle growth can lead to baldness. There are reasons to assume that connexin 26 regulates growth and differentiation through mechanisms unrelated to its function as a gap junction protein. Again, we see that the study of seemingly unrelated disorders of the hair follicle can shed new light on processes fundamental to life and death.