title: Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation.
abstract: We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone-shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF-kappaB essential modulator (NEMO) gene have recently been shown to be the cause of a group of ectodermal dysplasia and immunodeficiency disorders (EDA-ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G --> A(1027 + 5G --> A), which has not previously been described in EDA-ID. RT-PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C-terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled-coil motif (CC2), a leucin-zipper (LZ), and a zinc finger motif (ZF) sub-domains of NEMO. IkappaBalpha degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF-kappaB signaling. One healthy carrier had a completely skewed X-inactivation pattern with the normal X active, whereas the two other carriers had a random X-inactivation pattern. This family may represent a new phenotype within the EDA-ID disorders. From the heterogeneity in X-inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells.
authors.affiliation: Department of Medical Genetics, Forskningsveien 2B, Rikshospitalet, 0027 Oslo, Norway. k.h.orstavik@medisin.uio.no
authors.forename: Karen Helene
authors.initials: KH
authors.lastname: Ørstavik
authors.forename: Marianne
authors.initials: M
authors.lastname: Kristiansen
authors.forename: Gun Peggy
authors.initials: GP
authors.lastname: Knudsen
authors.forename: Kari
authors.initials: K
authors.lastname: Storhaug
authors.forename: Ashild
authors.initials: A
authors.lastname: Vege
authors.forename: Kristin
authors.initials: K
authors.lastname: Eiklid
authors.forename: Tore G
authors.initials: TG
authors.lastname: Abrahamsen
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
authors.forename: Jon
authors.initials: J
authors.lastname: Steen-Johnsen
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D041321:Chromosomes, Human, X / Q000235:genetics; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000473:pathology; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000473:pathology*; D008297:Male; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D010375:Pedigree; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: D020672:I-kappa B Proteins; C491731:IKBKG protein, human; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase