title: A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency.
abstract: Incontinentia pigmenti is an X-linked genodermatosis, lethal in males. Affected females survive because of X-chromosome dizygosity and negative selection of cells carrying the mutant X-chromosome, and for this reason the skewed X inactivation pattern is often used to confirm the diagnosis. The most frequent mutation is a deletion of part of the NEMO gene (NEMODelta4-10), although other mutations have been reported. Mutations of NEMO which do not abolish NF-kappaB activity totally permit male survival, causing an allelic variant of IP called hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). We present a non-classical IP female patient who also suffered transient immunodeficiency because of a late and progressive selection against peripheral blood cells carrying an active mutated X-chromosome. This finding suggests that in the absence of known mutation the X-inactivation studies used in genetic counselling can induce mistakes with some female patients. At the age of 3 years and 6 months, all immunodeficiency signs disappeared, and the X-chromosome inactivation pattern was completely skewed. The low T cell proliferation and CD40L expression corroborate the important role of NEMO/ NF-kappaB pathway in T cell homeostasis. The decreased NEMO protein amount and the impaired IkBalpha degradation suggest that this new mutation, NM_003639: c.1049dupA, causes RNA or protein instability. To our knowledge, this is the first time that selection against the mutated X-chromosome in X-linked disease has been documented in vivo.
authors.affiliation: Immunology Service, Hospital Universitari Son Dureta, Andrea Doria, 55, 07014, Palma de Mallorca, Balearic Islands, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Martinez-Pomar
authors.forename: Ivan
authors.initials: I
authors.lastname: Munoz-Saa
authors.forename: Damian
authors.initials: D
authors.lastname: Heine-Suner
authors.forename: Ana
authors.initials: A
authors.lastname: Martin
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
authors.forename: Nuria
authors.initials: N
authors.lastname: Matamoros
mesh_terms: D017668:Age of Onset; D049109:Cell Proliferation; D041321:Chromosomes, Human, X; D005260:Female; D005817:Genetic Counseling; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D007154:Immune System Diseases / Q000235:genetics*; D007184:Incontinentia Pigmenti / Q000235:genetics* / Q000473:pathology; D007223:Infant; D012075:Remission, Spontaneous; D013601:T-Lymphocytes
chemical_list: C491731:IKBKG protein, human; D051550:I-kappa B Kinase