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Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.

ABSTRACT: Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to ?-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

SUBMITTER: Marom R

PROVIDER: S-EPMC5599325 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.

Marom Ronit R Jain Mahim M Burrage Lindsay C LC Song I-Wen IW Graham Brett H BH Brown Chester W CW Stevens Servi J C SJC Stegmann Alexander P A APA Gunter Andrew T AT Kaplan Julie D JD Gavrilova Ralitza H RH Shinawi Marwan M Rosenfeld Jill A JA Bae Yangjin Y Tran Alyssa A AA Chen Yuqing Y Lu James T JT Gibbs Richard A RA Eng Christine C Yang Yaping Y Rousseau Justine J de Vries Bert B A BBA Campeau Philippe M PM Lee Brendan B

Human mutation 20170710 10

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region ...[more]

PMID: 28649782

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Project description:MicroRNAs (or miRNAs) are short nucleotide sequences (~17-22 bp long) that play important roles in gene regulation through targeting genes in the 3'untranslated regions (UTRs). Variants located in genomic regions might have different biological consequences in changing gene expression. Exonic variants (e.g., coding variant and 3'UTR variant) are often causative of diseases due to their influence on gene product. Variants harbored in the 3'UTR region where miRNAs perform their targeting function could potentially alter the binding relationships for target pairs, which could relate to disease causation. We gathered miRNA-mRNA targeting pairs from published studies and then employed the database of microRNA Target Site single nucleotide variants (SNVs) (dbMTS) to discover novel SNVs within the selected pairs. We identified a total of 183 SNVs for the 114 pairs of accurate miRNA-mRNA targeting pairs selected. Detailed bioinformatics analysis of the three genes with identified variants that were exclusively located in the 3'UTR section indicated their association with intellectual disability (ID). Our result showed an exceptionally high expression of GPR88 in brain tissues based on GTEx gene expression data, while WNT7A expression data were relatively high in brain tissues when compared to other tissues. Motif analysis for the 3'UTR region of WNT7A showed that five identified variants were well-conserved across three species (human, mouse, and rat); the motif that contains the variant identified in GPR88 is significant at the level of the 3'UTR of the human genome. Studies of pathways, protein-protein interactions, and relations to diseases further suggest potential association with intellectual disability of our discovered SNVs. Our results demonstrated that 3'UTR variants could change target interactions of miRNA-mRNA pairs in the context of their association with ID. We plan to automate the methods through developing a bioinformatics pipeline for identifying novel 3'UTR SNVs harbored by miRNA-targeted genes in the future.

Dataset Information

Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.

Publications

Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.

Similar Datasets

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