Dataset Information

Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability.

ABSTRACT: In a non-dysmorphic 5-year-old boy with developmental delay, well-controlled epilepsy, and microcephaly, a 234-kb deletion of Xp22.12 was detected by copy number analysis. The maternally inherited deletion removed the initial 15 of the 21 exons of the connector enhancer of KSR-2 gene called CNKSR2 or CNK2. Our finding suggests that loss of CNKSR2 is a novel cause of non-syndromic X-linked mental retardation, an assumption supported by high gene expression in the brain, localization to the post-synaptic density, and a role in RAS/MAPK-dependent signal transduction.

SUBMITTER: Houge G

PROVIDER: S-EPMC3326275 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability.

Houge G G Rasmussen I H IH Hovland R R

Molecular syndromology 20111220 2

In a non-dysmorphic 5-year-old boy with developmental delay, well-controlled epilepsy, and microcephaly, a 234-kb deletion of Xp22.12 was detected by copy number analysis. The maternally inherited deletion removed the initial 15 of the 21 exons of the connector enhancer of KSR-2 gene called CNKSR2 or CNK2. Our finding suggests that loss of CNKSR2 is a novel cause of non-syndromic X-linked mental retardation, an assumption supported by high gene expression in the brain, localization to the post-s ...[more]

PMID: 22511892

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Project description:Objective:Heterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability. Methods:Exome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits. Results:A novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits. Significance:The present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities.

Dataset Information

Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability.

Publications

Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability.

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