Journal Article

Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel <i>NEMO</i> mutations interfering with NF-κB activation

Francesca Fusco, Tiziana Bardaro, Giorgia Fimiani, Vincenzo Mercadante, Maria Giuseppina Miano, Geppino Falco, Alain Israël, Gilles Courtois, Michele D'Urso and Matilde Valeria Ursini

in Human Molecular Genetics

Volume 13, issue 16, pages 1763-1773
Published in print August 2004 | ISSN: 0964-6906
Published online June 2004 | e-ISSN: 1460-2083 | DOI:
Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-κB activation

Show Summary Details


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-κB essential modulator (NEMO) gene, responsible for IP, encodes the regulatory subunit of the IκB kinase (IKK) complex required for nuclear factor κB (NF-κB) 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-κB 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-κB activation following lipopolysaccharide stimulation. Mutations that disrupt the C-terminal domain, required for the recruitment of upstream factors, showed lower or no NF-κB 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-κB.

Journal Article.  7370 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.