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

Matilde Immacolata Conte, Alessandra Pescatore, Mariateresa Paciolla, Elio Esposito, Maria Giuseppina Miano, Maria Brigida Lioi, Maeve A. Mcaleer, Giuliana Giardino, Claudio Pignata, Alan D. Irvine, Angela E. Scheuerle, Ghislaine Royer, Smail Hadj-Rabia, Christine Bodemer, Jean Paul Bonnefont, Arnold Munnich, Asma Smahi, Julie Steffann, Francesca Fusco, Matilde Valeria Ursini

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)165-177
Number of pages13
JournalHuman mutation
Issue number2
StatePublished - Feb 2014


  • Genomic rearrangements
  • Incontinentia Pigmenti
  • NEMO
  • NF-kB pathway

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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