Human Molecular Genetics Advance Access originally published online on June 30, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 16 1763-1773
DOI: 10.1093/hmg/ddh192
Human Molecular Genetics, Vol. 13, No. 16 © Oxford University Press 2004; all rights reserved
Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-
B activation
1Institute of Genetics and Biophysics, Adriano Buzzati Traverso-CNR, Naples, Italy and 2Unité de Biologie Moléculaire de l' Expression Génique, Institut Pasteur, Paris, France
Received April 8, 2004; Revised May 25, 2004; Accepted June 11, 2004
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-
B essential modulator (NEMO) gene, responsible for IP, encodes the regulatory subunit of the IB kinase (IKK) complex required for nuclear factor B (NF-B) 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-B 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-B activation following lipopolysaccharide stimulation. Mutations that disrupt the C-terminal domain, required for the recruitment of upstream factors, showed lower or no NF-B 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-B.
* To whom correspondence should be addressed. Email: ursini{at}igb.cnr.it
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