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Insight into IKBKG / NEMO Locus: Report of New Mutations and Complex Genomic Rearrangements Leading to Incontinentia Pigmenti Disease
Author(s) -
Conte Matilde Immacolata,
Pescatore Alessandra,
Paciolla Mariateresa,
Esposito Elio,
Miano Maria Giuseppina,
Lioi Maria Brigida,
McAleer Maeve A.,
Giardino Giuliana,
Pignata Claudio,
Irvine Alan D.,
Scheuerle Angela E.,
Royer Ghislaine,
HadjRabia Smail,
Bodemer Christine,
Bonnefont JeanPaul,
Munnich Arnold,
Smahi Asma,
Steffann Julie,
Fusco Francesca,
Ursini Matilde Valeria
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22483
Subject(s) - biology , frameshift mutation , genetics , indel mutation , incontinentia pigmenti , locus (genetics) , missense mutation , mutation , gene , single nucleotide polymorphism , genotype
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 nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent 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 microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining 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), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five 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, accessible at http://IKBKG.lovd.nl.