Combination of Linkage Mapping and Microarray- Expression Analysis Identifies NF-κB Signaling Defect as a Cause of Autosomal-Recessive Mental Retardation.

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 consan- guineous Tunisian family of three MR children with mild microcephaly and white-matter abnormalities identified the TRAPPC9 gene, which encodes a NF-κB-inducing kinase (NIK) and 1κB kinase complex β (IKK-β) binding protein, as a likely candidate. Sequencing analysis revealed a nonsense variant (c. 1 708C>T [p.R5 70X]) within exon 9 of this gene that is responsible for an undetectable level of TRAPPC9 protein in patient skin fibroblasts. Moreover, TNF-α stimulation assays showed a defect in lkBα degradation, suggesting impaired NF-κB signaling in patient cells. This study provides evidence of an NF-κB signaling defect in isolated MR. [ABSTRACT FROM AUTHOR]