Genotype-phenotype correlation in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kB activation.

Incontinentia Pigmenti (IP) is an X-linked genodermatosis, lethal for males and presents in females with abnormal skin pigmentation and high variable clinical signs. NEMO gene, responsible for IP, encodes the regulatory subunit of the IKK complex for NF-kB activation. We analyzed NEMO in 122 IP patients from EC and identified mutations in 83 (36 familiar and 47 sporadic cases). However, NEMO mutations isolated in this study account for the majority but not all clinical cases. The recurrent NEMO 4-10 deletion that is the major cause of the disease was present in 73 females. In addition 10 point alterations were identified. A phenotype scoring system was used for correlation between the mutation type and the clinical IP presentation. To assess genotype-phenotype correlation in IP patients we listed features that are typical for IP but not consistent in all patients and could therefore reflect the severity of the syndrome. For calculating the score we included only defects relative to nervous system, eyes, teeth, hair and nail, that are most frequently, but not always, observed in IP patients. If a genotype-phenotype correlation does exist, females who carry loss-of-function mutations would be expected to have the most severe phenotype. In our study, however, this is not the case: 50 patients with the same exon 4-10 NEMO deletion have severity score ranging from 1 to 8. In addition, we found that mutations preserving some activity (i.e. same point mutations) show an atypical phenotype characterized by involvement of much more tissues than classical IP phenotype. Thus, the detected mutation spectrum do not allow genotypephenotype correlation, leading to the hypothesis that other factors may modulate the IP pathogenesis. 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.