Human Molecular Genetics, 2001, Vol. 10, No. 19 2171-2179
© 2001 Oxford University Press
A recurrent deletion in the ubiquitously expressed NEMO (IKK-
) gene accounts for the vast majority of incontinentia pigmenti mutations
1Department of Molecular and Human Genetics, 2Department of Dermatology and 3Department of Ophthalmology and the Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA, 4Wellcome Trust Centre for Molecular Mechanisms of Disease and University of Cambridge Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK, 5International Institute of Genetics and Biophysics, Area di Ricerca del CNR di Napoli, Naples, Italy, 6BioGem, Naples, Italy and 7Department of Genetics, Unité des Recherches sur les Handicaps Génétiques de l’Enfant INSERM-393, Hopital Necker-Enfants Malades, 75015 Paris, France
Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by abnormal skin pigmentation, retinal detachment, anodontia, alopecia, nail dystrophy and central nervous system defects. This disorder segregates as a male lethal disorder and causes skewed X-inactivation in female patients. IP is caused by mutations in a gene called NEMO, which encodes a regulatory component of the I
B kinase complex required to activate the NF-B pathway. Here we report the identification of 277 mutations in 357 unrelated IP patients. An identical genomic deletion within NEMO accounted for 90% of the identified mutations. The remaining mutations were small duplications, substitutions and deletions. Nearly all NEMO mutations caused frameshift and premature protein truncation, which are predicted to eliminate NEMO function and cause cell lethality. Examination of families transmitting the recurrent deletion revealed that the rearrangement occurred in the paternal germline in most cases, indicating that it arises predominantly by intrachromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogenesis and is expressed ubiquitously. These data confirm the involvement of NEMO in IP and will help elucidate the mechanism underlying the manifestation of this disorder and the in vivo function of NEMO. Based on these and other recent findings, we propose a model to explain the pathogenesis of this complex disorder.
+ To whom correspondence should be addressed. Tel: +1 713 798 4787; Fax: +1 713 798 5386; Email: nelson@bcm.tmc.edu The authors are members of the International IP ConsortiumThe authors wish it to be known that, in their opinion, Swaroop Aradhya, Hayley Woffendin, Tiziana Bardaro and Asmae Smahi should be regarded as joint First Authors
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