Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to Incontinentia pigmenti disease

Incontinentia Pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of NF-kB signaling. In more than 80% of cases, IP is due to recurrent or non-recurrent deletions causing Loss-of-Function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new micro-indel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair Fork-Stalling-and-Template-Switching (FoSTeS) and Microhomology-Mediated-End-Joining (MMEJ) mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), while 7/21 predict a partial loss of NEMO/IKKgamma activity (2 splicing and 5 missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP-disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants,