title: Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation.
abstract: Autosomal-recessive inheritance accounts for nearly 25% of nonsyndromic mental retardation (MR), but the extreme heterogeneity of such conditions markedly hampers gene identification. Combining autozygosity mapping and RNA expression profiling in a consanguineous Tunisian family of three MR children with mild microcephaly and white-matter abnormalities identified the TRAPPC9 gene, which encodes a NF-kappaB-inducing kinase (NIK) and IkappaB kinase complex beta (IKK-beta) binding protein, as a likely candidate. Sequencing analysis revealed a nonsense variant (c.1708C>T [p.R570X]) within exon 9 of this gene that is responsible for an undetectable level of TRAPPC9 protein in patient skin fibroblasts. Moreover, TNF-alpha stimulation assays showed a defect in IkBalpha degradation, suggesting impaired NF-kappaB signaling in patient cells. This study provides evidence of an NF-kappaB signaling defect in isolated MR.
authors.affiliation: INSERM U781, Département de Génétique and Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Orianne
authors.initials: O
authors.lastname: Philippe
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.forename: Astrid
authors.initials: A
authors.lastname: Carioux
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Plaza
authors.forename: Philippe
authors.initials: P
authors.lastname: Guigue
authors.forename: Florence
authors.initials: F
authors.lastname: Molinari
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase