A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) 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, nai l 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 regulato ry component of the I kappaB kinase complex required to activate the NF-kap paB pathway. Here we report the identification of 277 mutations in 357 unre lated IP patients. An identical genomic deletion within NEMO accounted for 90% of the identified mutations. The remaining mutations were small duplica tions, substitutions and deletions. Nearly all NEMO mutations caused frames hift and premature protein truncation, which are predicted to eliminate NEM O function and cause cell lethality. Examination of families transmitting t he recurrent deletion revealed that the rearrangement occurred in the pater nal germline in most cases, indicating that it arises predominantly by intr achromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogene sis and is expressed ubiquitously. These data confirm the involvement of ME MO 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 othe r recent findings, we propose a model to explain the pathogenesis of this c omplex disorder.