Search

Incontinentia Pigmenti (IP) is a rare X-linked dominant neuroectodermal disorder caused by mutations in the nuclear factor kappaB essential modulator (NEMO)/Inhibitor of Kappa light polypeptide gene enhancer in B-cells Kinase Gamma (IKBKG) gene. The NEMO locus maps in a region with a unique genomic organisation: in the centromeric direction, NEMO partially overlaps the glucose-6-phosphate dehydrogenase gene; in the telomeric direction, NEMO is part of a 35.7 kb segmental duplication containing its nonfunctional truncated copy pseudoNEMO. Moreover, a high frequency of micro-/macro-homologies, tandem repeats and repeat/repetitive sequences characterise the local architecture of the locus increasing its vulnerability to the production of de novo genomic rearrangements through different mechanisms. Indeed, instances of nonallelic homologous recombination (NAHR) causing both benign and pathological alleles, nonhomologous end joining (NHEJ) and Alu–Alu-mediated recombination events producing either recurrent or nonrecurrent deletions have been reported. These events, occurring during both meiosis and mitosis, reveal that the region is prone to generate complex human genomic rearrangements. Key Concepts: Genomic rearrangements in the NEMO gene can be generated during meiosis or mitosis. Low copy repeats or segmental duplication regions can act as substrates for aberrant recombination and for gene conversion events. The complex architecture of the locus enhances its vulnerability to the production of de novo genomic rearrangements through different mechanisms. The mutational mechanisms that can give rise to genomic rearrangements in the IP locus are: NAHR, NHEJ, Alu–Alu mediated recombination and gene conversion. NAHR, mediated through sequences that exhibit a considerable homology called MER67B, is one of the major mechanisms for the generation of de novo rearrangements in the IP locus. Keywords: incontinentia pigmenti; NEMO/IKBKG locus; pseudogene; G6PD; NAHR; NHEJ; Alu–Alu recombination; genomic rearrangement; deletion; duplication