title: Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease.
abstract: 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.
authors: Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', IGB-CNR, Naples, Italy.
authors: Matilde Immacolata
authors: MI
authors: Conte
authors: Alessandra
authors: A
authors: Pescatore
authors: Mariateresa
authors: M
authors: Paciolla
authors: Elio
authors: E
authors: Esposito
authors: Maria Giuseppina
authors: MG
authors: Miano
authors: Maria Brigida
authors: MB
authors: Lioi
authors: Maeve A
authors: MA
authors: McAleer
authors: Giuliana
authors: G
authors: Giardino
authors: Claudio
authors: C
authors: Pignata
authors: Alan D
authors: AD
authors: Irvine
authors: Angela E
authors: AE
authors: Scheuerle
authors: Ghislaine
authors: G
authors: Royer
authors: Smail
authors: S
authors: Hadj-Rabia
authors: Christine
authors: C
authors: Bodemer
authors: Jean-Paul
authors: JP
authors: Bonnefont
authors: Arnold
authors: A
authors: Munnich
authors: Asma
authors: A
authors: Smahi
authors: Julie
authors: J
authors: Steffann
authors: Francesca
authors: F
authors: Fusco
authors: Matilde Valeria
authors: MV
authors: Ursini
mesh_terms: D000818:Animals; D001483:Base Sequence; D041321:Chromosomes, Human, X; D018389:Codon, Nonsense; D016368:Frameshift Mutation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism*; D007184:Incontinentia Pigmenti / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: D018389:Codon, Nonsense; C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase
keywords: IKBKG; Incontinentia Pigmenti; NEMO; NF-kB pathway; genomic rearrangements