A recurrent deletion in the ubiquitously expressed NEMO (IKK-γ) gene accounts for the vast majority of incontinentia pigmenti mutations

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...

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Bibliographic Details
Published in:Human molecular genetics 2001-09, Vol.10 (19), p.2171-2179
Main Authors: ARADHYA, Swaroop, WOFFENDIN, Hayley, LEWIS, Richard A, KENWRICK, Sue, NELSON, David L, JAKINS, Tracy, BARDARO, Tiziana, ESPOSITO, Teresa, SMAHI, Asmae, SHAW, Christine, LEVY, Moise, MUNNICH, Arnold, D'URSO, Michele
Format: Article
Language:English
Subjects:
anodontia
Biological and medical sciences
Blotting, Northern
Blotting, Southern
Carrier Proteins
Chromosome Aberrations
Cohort Studies
DNA Primers - chemistry
Exons
Female
Fundamental and applied biological sciences. Psychology
Gene Deletion
Humans
I-kappa B Kinase
I^KB protein
Incontinentia pigmenti
Incontinentia Pigmenti - enzymology
Incontinentia Pigmenti - genetics
Male
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
Molecular and cellular biology
Mutation
NEMO gene
Phenotype
Polymerase Chain Reaction
Polymorphism, Genetic
retinal detachment
Reverse Transcriptase Polymerase Chain Reaction
X Chromosome - physiology
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Summary: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 IkappaB kinase complex required to activate the NF-kappaB 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.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/10.19.2171