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. 2017 Oct;38(10):1365-1371.
doi: 10.1002/humu.23282. Epub 2017 Jul 10.

Heterozygous Variants in ACTL6A, Encoding a Component of the BAF Complex, Are Associated With Intellectual Disability

Free PMC article

Heterozygous Variants in ACTL6A, Encoding a Component of the BAF Complex, Are Associated With Intellectual Disability

Ronit Marom et al. Hum Mutat. .
Free PMC article


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 β-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.

Keywords: ACTL6A; BAF complex; intellectual disability; speech delay.

Conflict of interest statement

Conflicts of Interest

The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical testing done at Baylor Genetics Laboratories.


Figure 1
Figure 1. Clinical photographs of subjects and summary of ACTL6A pathogenic variants
(A) Subject 1 at age 7 years, demonstrating coarse facial features with broad nasal tip (a), broad fingers and toes with dystrophic nails, and short distal phalanges (b, c); Subject 2 at age 6 years, demonstrating elongated face with large forehead, narrow eyelids, broad nasal tip and poorly developed philtrum ridge (d); and Subject 3 at age 6 years, showing prominent high forehead, low set everted ears, narrow eyelids, broad nasal tip, and small chin (e). Note digital anomalies, including overriding second toe, clinodactyly of 3rd–5th toes and sandal gap (f). The photographs of Subject 1 were reproduced with permission from the American Journal of Medical Genetics, Part A (Brautbar, et al., 2009). (B) Annotation of the two amino acid residues in exons 8 and 13 affected in Subjects 1 and 2, and the splicing variant causing in-frame deletion of exon 13 in Subject 3. Conservation across species is shown for the three variants. (C) ACTL6A protein structure model as predicted by I-TASSER server ( (Zhang, 2008) and visualized using Swiss-Pdb viewer ( (Guex and Peitsch, 1997), showing localization of the mutated amino acids in Subjects 1 and 2 (yellow arrows), and the deleted exon 13 in Subject 3 (red ribbon). Previous study (Nishimoto, et al., 2012) demonstrated that M1 and M2 mutants of human ACTL6A exhibit impaired binding capacity to beta actin (ACTB) and BRG1/SMARCA4, and thus disrupt ACTL6A recruitment to the BAF complex. This data supports a deleterious effect for p.Glu227Gln (E227Q/M1) and p.Arg377Trp (R377W/M2) on ACTL6A protein function.
Figure 2
Figure 2. RNA, protein and cell cycle studies in Subject 3 lymphoblasts encompassing a heterozygous ACTL6A splicing variant
(A) RT-PCR amplification of the full-length cDNA from control sample (2) shows two transcripts due to alternative splicing at ACTL6A exon 1, while amplification of Subject 3 cDNA (1) shows four transcripts. PCR-cloning and sequencing, followed by alignment of the sequence results with ACTL6A mRNA sequence demonstrates that two of the four transcripts in Subject 3 correspond to expression of the two isoforms of wild-type allele, and two transcripts correspond to expression of the two isoforms of mutated allele containing an in-frame deletion of the full length of exon 13. (B) Western blot analysis of ACTL6A protein expression in Subject 3 and control cells, revealing reduced protein expression in Subject 3 cells that is suggestive of a haploinsufficiency mechanism. (C) Immunoprecipitation (IP) with anti-ACTL6A antibody, showing decreased interaction with BRG1 in subject cells (Subject 3) compared to unrelated healthy control (Control). There was no binding to negative control (rabbit IgG). Immunoblot (IB) was quantified (using ImageJ program), showing 85% reduction in co-IP efficiency, presented here as % of control. The reduction of co-IP efficiency was repeated in two other independent experiments (showing 70% and 20% reduction, respectively). (D) Cell cycle analysis of cells from Subject 3 and control cells. As compared to control, a smaller fraction of cells from subject 3 resided in G2 phase (10.5 % vs. 16.8 % in control samples). This trend was observed in two independent experiments and is consistent with previous reports describing cell cycle perturbation in ACTL6A-depleted cells (Lee, et al., 2007).

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