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Human Molecular Genetics Advance Access published online on June 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh192
© 2004 by Oxford University Press
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Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kB activation

Francesca Fusco 1, Tiziana Bardaro 1, Giorgia Fimiani 1, Vincenzo Mercadante 1, Maria Giuseppina Miano 1, Geppino Falco 1, Alain Israël 2, Gilles Courtois 3, Michele D'Urso 1, Matilde Valeria Ursini 1*

1 Institute of Genetics and Biophysics, Adriano Buzzati Traverso-CNR, Naples- Italy
2 Unité de Biologie Moléculaire de l' Expression Génique, Institut Pasteur, Paris, France
3 Unité de Biologie Moléculaire de l' Expression Génique, Institut Pasteur, Paris, France; INSERM U532, Hôpital Saint-Louis, Paris, France

* To whom correspondence should be addressed. E-mail: ursini{at}igb.cnr.it.


  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 NEMO gene, responsible for IP, encodes the regulatory subunit of the IKK complex required for NF-kB 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: 3 frameshift, 3 nonsense, 3 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(-) 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 LPS 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.


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