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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.

SUBMITTER: Philippe O 

PROVIDER: S-EPMC2795800 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation.

Philippe Orianne O   Rio Marlène M   Carioux Astrid A   Plaza Jean-Marc JM   Guigue Philippe P   Molinari Florence F   Boddaert Nathalie N   Bole-Feysot Christine C   Nitschke Patrick P   Smahi Asma A   Munnich Arnold A   Colleaux Laurence L  

American journal of human genetics 20091201 6

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 lik  ...[more]

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