Investigating the Molecular Genetics of Skin Diseases

Our laboratory has been investigating for the past 20 years the genetic basis of skin disorders. Monogenic skin disorders are known to be prevalent among Middle Eastern populations, and at this regard, our laboratory is ideally situated to carry research in that field. These efforts have led to the deciphering of the molecular basis of more than 25 genetic diseases by members of our group. The deciphering of the molecular basis of a monogenic disorder invariably reveals a novel pathway whose importance is exemplified by the disease resulting from its malfunction. Accordingly, over the years we have uncovered a number of novel biochemical pathways of importance for the physiology of the skin and other organs including kidney, eye and central nervous system. We systematically explore the mechanistic aspects of these new pathways using almost exclusively humanized models such as three-dimensional skin equivalents, hair organ cultures and chimeric mouse models. We have for example identified the role of filaggrin 2 in the pathogenesis of a large series of seemingly unrelated diseases featuring peeling of the skin. Once the function of a novel gene product is established, this new knowledge can be translated in the form of new treatments for rare and more common diseases alike. For example, we have found that aminoglycosides promote read-through across a nonsense mutation responsible for a rare form of congenital hair loss. We have subsequently showed that topical gentamycin can foster hair growth in patients affected with this condition. Based on a similar paradigm we are also investigating the genetic basis of complex skin traits including psoriasis and pemphigus, a dreadful autoimmune disorder associated with 90% mortality if left untreated. We have revealed a new pathway associated with an increased risk for pemphigus and are now attempting at exploiting this discovery to develop novel approaches to the management of this condition.

Oscillating between bedside and the bench, our research program is substantiating a major goal of our division, the integration of research and clinical care to the benefit of our patients. Our research program's main objectives are:

1. Delineation of the genetic basis of inherited skin disorders using a palette of analytical tools.
2. Systematic investigation of the function of novel genes found to be associated with inherited skin diseases using humanized models such as three-dimensional artificial skin equivalents, hair organ cultures and chimeric mice.
3. Translation of this new knowledge into treatments for rare and more common diseases using engineered reporter cell lines and robotic small molecule library screening followed by in vitro and in vivo validation of relevant hits.