TY - JOUR
T1 - Insight into IKBKG/NEMO locus
T2 - Report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease
AU - Conte, Matilde Immacolata
AU - Pescatore, Alessandra
AU - Paciolla, Mariateresa
AU - Esposito, Elio
AU - Miano, Maria Giuseppina
AU - Lioi, Maria Brigida
AU - Mcaleer, Maeve A.
AU - Giardino, Giuliana
AU - Pignata, Claudio
AU - Irvine, Alan D.
AU - Scheuerle, Angela E.
AU - Royer, Ghislaine
AU - Hadj-Rabia, Smail
AU - Bodemer, Christine
AU - Bonnefont, Jean Paul
AU - Munnich, Arnold
AU - Smahi, Asma
AU - Steffann, Julie
AU - Fusco, Francesca
AU - Ursini, Matilde Valeria
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Genomic rearrangements
KW - IKBKG
KW - Incontinentia Pigmenti
KW - NEMO
KW - NF-kB pathway
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U2 - 10.1002/humu.22483
DO - 10.1002/humu.22483
M3 - Article
C2 - 24339369
AN - SCOPUS:84891932026
SN - 1059-7794
VL - 35
SP - 165
EP - 177
JO - Human mutation
JF - Human mutation
IS - 2
ER -