Molecular Analysis of Xq28-Linked Incontinentia Pigmenti
Incontinentia Pigmenti (MIM 308300) is a complex human disorder that affects various organs, including the skin and the visual, nervous, immune, vascular, and skeletal systems. The disorder is usually lethal in males; female patients survive because cells that express the mutant X-chromosome are eliminated, leaving cells with an active normal X-chromosome to proliferate.
Under the initial funding of this project we demonstrated that IP female subjects carry mutations in the NEMO (IKK- g) gene. The NEMO protein is responsible for regulating NF-kB-dependent signal transduction. Mutations in NEMO lead to absence of NF-kB activity, which renders cells vulnerable to apoptosis, explaining both the male lethality and skewed X-inactivation in surviving females. Most IP females carry an identical deletion that occurs due to misalignment between two intragenic repeat elements; the remaining patients carry microdeletions, duplications, point mutations, and substitutions. We have demonstrated that some male individuals can survive with hypomorphic NEMO mutations that are not lethal to cells. An interesting genomic architecture is found at the NEMO locus: the gene has been duplicated locally together with an adjacent gene, LAGE2 . This NEMO/LAGE2 duplication appears susceptible to several genomic rearrangements. All these findings have contributed substantively to understanding the genetic basis of IP, the functions of the NF-kB pathway, and the genomic nature of the NEMO region. Results in the initial funding of this project have signaled several new and challenging questions, which will be addressed by the aims proposed here.
Absence of NEMO prevents NF-kB from activating the transcription of downstream genes, many of which remain undiscovered. Knockout mouse models have not been useful in studying the entire IP phenotype due to loss of mutant cells in female and male embryonic lethality. In humans, hypomorphic alleles are compatible with cellular survival and result in an IP-like phenotype. These mutations allow some male individuals to survive but with variant phenotypes because the consequences of disrupted NF-kB activity are fully exposed. Hypomorphic mutations, along with conditional mutations, will be valuable to examine the role of NEMO during development. In addition to the phenotype, IP's other interesting characteristic is that NEMO has been duplicated. Whether the second copy of NEMO has a specific role in the pathogenesis of IP has not been examined. The nature of the NEMO region will also provide insight into genomic stability and chromosomal backgrounds that confer susceptibility to rearrangements. To address these issues, this project focuses on characterizing mutations in IP patients, evaluating hypomorphic and conditional Nemo mutations in mouse models, elucidating the regulatory control imposed on NEMO , and determining the significance of ?NEMO and of genomic rearrangements at the NEMO/LAGE2 duplication.
Relevance of the project to IDDRC mission:
Mental Retardation is found in a fraction of girls with IP. NEMO mutation has neurological effects.