Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF- B activation

Institute of Genetics and Biophysics, Adriano Buzzati Traverso-CR, Naples, Italy.
Human Molecular Genetics (Impact Factor: 6.39). 08/2004; 13(16):1763-73. DOI: 10.1093/hmg/ddh192
Source: PubMed


Incontinentia Pigmenti (IP) is an X-linked genodermatosis that is lethal for males and present in females with abnormal skin pigmentation and high variable clinical signs, including retinal detachment, anodontia, alopecia, nail dystrophy and nervous system defects. The NF-kappaB essential modulator (NEMO) gene, responsible for IP, encodes the regulatory subunit of the IkappaB kinase (IKK) complex required for nuclear factor kappaB (NF-kappaB) activation. We analyzed the NEMO gene in 122 IP patients and identified mutations in 83 (36 familiar and 47 sporadic cases). The recurrent NEMO exon 4-10 deletion that is the major cause of the disease was present in 73 females (59.8%). In addition 10 point alterations (8.2% of females) were identified: three frameshift, three nonsense, three missense and one in-frame deletion of a single amino acid. We measured the effects of these NEMO point-mutations on NF-kappaB signaling in nemo(-/-) deficient murine pre-B cells. A mutation in the N-terminal domain, required for IKK assembly, reduced but did not abolish NF-kappaB activation following lipopolysaccharide stimulation. Mutations that disrupt the C-terminal domain, required for the recruitment of upstream factors, showed lower or no NF-kappaB activation. A phenotype score based on clinical features of our IP patients was applied for summarizing disease severity. The score did not correlate with mutation type or domain affected indicating that other factors influence the severity of IP. Such a factor is likely to be X-inactivation. Indeed, 64% of our patients have extremely skewed X-inactivation pattern (>/=80 : 20). Overall IP pathogenesis thus depends on a combination of X-inactivation and protein domain that recruit upstream factors and activate NF-kappaB.

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    • "IP has also been diagnosed in males with a 47,XXY karyotype (Klinefelter syndrome) [19]. The large heterogeneity of defects, the severe clinical presentations, and the wide spectrum of IKBKG/NEMO alterations [7,11,14,20] makes the selection of homogeneous groups of patients difficult, precluding any therapeutic approaches. Indeed, despite the considerable progress that has been made in detailing the basic pathology of the IP disorder, the gap between research and clinical care has remained wide. "
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    ABSTRACT: We report here on the building-up of a database of information related to 386 cases of Incontinentia Pigmenti collected in a thirteen-year activity (2000-2013) at our centre of expertise. The database has been constructed on the basis of a continuous collection of patients (27.6/year), the majority diagnosed as sporadic cases (75.6%). This activity has generated a rich source of information for future research studies by integrating molecular/clinical data with scientific knowledge. We describe the content, architecture and future utility of this collection of data on IP to offer comprehensive anonymous information to the international scientific community.
    Full-text · Article · Jun 2014 · Orphanet Journal of Rare Diseases
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    • "The most well-known gene in the duplicated region was the IKBKG gene (NEMO; MIM 300248). IKBKG encodes for I Kappa Kinase (IKK), a regulatory subunit that activates immune modulator NFkB (Fusco et al., 2004). Hence, mutations in IKBKG lead to immunodeficiency in most cases. "
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    ABSTRACT: Duplications on Xq28 are common, although quite variable in size, but usually include the MECP2 gene. Here, we present a patient with a unique, small, 167-kb duplication at Xq28, not including MECP2. The most important gene in the duplicated region was IKBKG, mutations in which can cause a variety of distinct syndromes. Our patient's symptoms overlapped with different IKBKG-associated phenotypes, including hypohidrotic ectodermal dysplasia, incontinentia pigmenti, immunodeficiency, recurrent isolated invasive pneumococcal disease and anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema. In addition, she also had peripheral neuropathy, gastroparesis and various benign tumors, but no intellectual disability. Mixed syndromal presentation in several patients with IKBKG defect implies that IKBKG-related phenotypes are more like a spectrum, rather than distinct syndromes. We also suggest our patient's multisystem phenotype to be a novel contiguous gene syndrome, in which the key features include immune deficiency, macrocephaly, skin abnormalities, gastroparesis, peripheral small-fiber neuropathy, and benign tumors.
    Full-text · Article · Apr 2014 · Clinical dysmorphology
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    • "p.Arg173GlyfsX108 Exon 4 Frameshift ND IP [Aradhya et al., 2001c] 17 c.518+2T>A ND Intron 4 Splice site ND IP [Aradhya et al., 2001c] 18 c.523dup p.Arg175ProfsX13 Exon 5 Frameshift ND IP [Aradhya et al., 2001c] 19 c.G549C p.Gln183His Exon 5 Missense S IP [Hsiao et al., 2010] 20 c.551 588del p.Leu184ArgfsX57 Exon 5 Frameshift ND IP [Aradhya et al., 2001c] 21 c.570del p.Leu191CysfsX90 Exon 5 Frameshift ND IP [Aradhya et al., 2001c] 22 c.638 642dup p.Met215SerfsX68 Exon 5 Frameshift ND IP [Aradhya et al., 2001c] 23 c.639 645del p.Arg214SerfsX65 Exon 5 Frameshift ND IP [Aradhya et al., 2001c] 24 c.662C>A p.Ser221X Exon 5 Nonsense ND IP [Fusco et al., 2008] 25 c.706C>T p.Gln236X Exon 6 Nonsense S IP [Aradhya et al., 2001c] 26 c.715C>T p.Gln239X Exon 6 Nonsense S IP [Fusco et al., 2004] 27 c.723C>G p.Tyr241X Exon 6 Nonsense ND IP [Aradhya et al., 2001c] 28 c.766C>T p.Arg256X Exon 6 Nonsense F IP [Fusco et al., 2008] 29 c.792dup p.Gln265ThrfsX19 Exon 7 Frameshift S IP [Martinez-Pomar et al., 2005]. 30 c.868C>T p.Gln290 X Exon 7 Nonsense ND IP [Aradhya et al., 2001c] "
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    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
    Full-text · Article · Feb 2014 · Human Mutation
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