http://www.cnr.it/ontology/cnr/individuo/prodotto/ID26662
Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappa B activation (Articolo in rivista)
- Type
- Label
- Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappa B activation (Articolo in rivista) (literal)
- Anno
- 2004-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1093/hmg/ddh192 (literal)
- Alternative label
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Fusco F.; Bardaro T.; Fimiani G.; Mercadante V.; Miano M.G.; Falco G.; Israel A.; Courtois G.; D'Urso M.; Ursini M.V. (literal)
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- Note
- ISI Web of Science (WOS) (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- Institute of Genetics and Biophysics, Adriano Buzzati Traverso-CNR, Naples, Italy and Unite´de Biologie
Moleculaire de l' Expression Genique, Institut Pasteur, Paris, France (literal)
- Titolo
- Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappa B activation (literal)
- Abstract
- 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-kB essential modulator (NEMO) gene, responsible
for IP, encodes the regulatory subunit of the IkB kinase (IKK) complex required for nuclear factor kB (NFkB)
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-kB signaling in nemo(2/2) deficient murine pre-B cells. A
mutation in the N-terminal domain, required for IKK assembly, reduced but did not abolish NF-kB activation
following lipopolysaccharide stimulation. Mutations that disrupt the C-terminal domain, required for the
recruitment of upstream factors, showed lower or no NF-kB 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-kB. (literal)
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