UNRAVELLING THE MOLECULAR MECHANISMS OF IMPAIRED NEMO FUNCTION IN IP PATHOGENESIS

The disorder that provides the best insight into the NF-kB pathway is Incontinentia Pigmenti (IP), an X-linked dominant and male-lethal disease. Heterozygous IP females can survive owing to X-inactivation mosaicism and present neonatal rush, and frequently malformations of eyes, teeth and central nervous system. NEMO, whose mutations are causative of IP, encodes a crucial regulatory protein responsible for NF-kB activation, a transcription factor of universal importance being involved in many cellular functions including immune response, cell survival and neuronal plasticity. NEMO is the point of convergence for many NF-kB inducers. IP pathogenesis is due to mutations that impair every functional domain of this protein. Loss-of-function mutations of NEMO account for 60% of IP patients. Mutations of NEMO that only reduce its function cause IP in heterozygous females and Ectodermal Dysplasia associated with immunological defects (EDA-ID) in hemizygous males. The genetic defect has only been identified in 70% of the IP patients. Thus, the frequency of NEMO mutations is underestimated, and/or the contribution of other genes still remains to be established. The overall objective of this proposal is to contribute in ameliorate our understanding of the genetic and pathological aspects of NF-kB related diseases paying a special attention to reveal all the molecular interactions involving NEMO protein that are affected in IP, in particular in the Central Nervous System. The elucidation not only of the NEMO mutations but also of the functional consequences of such mutations causing IP will help to establish the exact mechanism of the disease and to devise the new treatments that will change patient life.