Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCD1
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:50,085,342-50,100,707 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | Coffin-Siris syndrome 11 | 618779 | Autosomal dominant | 3 |
The SMARCD1 gene encodes BAF60A, a subunit of the SWI/SNF chromatin remodeling complex, which is a highly conserved protein complex that utilizes energy from ATP to alter nucleosome-DNA interactions; this alteration results in more open chromatin for transcription-factor binding that can affect gene expression. The cell-specific neuronal progenitor (np) and neuronal (n) BAF subunits are important for the regulation of gene-expression programs involved in neuronal differentiation and brain-region specification, as well as being essential in mature neurons for memory formation, synaptic plasticity, and activity-responsive neurite outgrowth (summary by Wang et al., 1996 and Nixon et al., 2019).
See also BAF155 (601732) and BAF170 (601734), other subunits in this complex.
Wang et al. (1996) isolated a SWI/SNF complex from the human YT cell line that was analogous to the yeast complex. They found that the resultant complexes are composed of 9 to 12 polypeptides, which they termed BAFs (for BRG1-associated factors). Wang et al. (1996) isolated the BAF60a subunit, which encodes a polypeptide of 435 amino acids and is homologous to the yeast SWP73 gene. The authors used BAF60a as a probe to isolate 2 closely related homologs, BAF60b (601736) and BAF60c (601737).
By PCR of a somatic cell hybrid panel and radiation hybrid analysis, Ring et al. (1998) mapped the SMARCD1 gene to chromosome 12q13-q14.
In 5 unrelated children with Coffin-Siris syndrome-11 (CSS11; 618779), Nixon et al. (2019) identified heterozygous mutations in the SMARCD1 gene (601735.0001-601735.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were confirmed to be de novo in patients 2-5; paternal DNA was not available from patient 1. There were 3 missense and 2 nonsense mutations, and all clustered close to or in the C terminus. Both nonsense mutations were predicted to escape nonsense-mediated mRNA decay, although RNA analysis of patient cells was not performed. In vitro functional expression studies using expression constructs of the 3 missense variants (D330E, W486X, and F495L) showed that the mutant proteins were expressed at normal levels and did not abolish the interaction of SMARCD1 with at least 2 other complex subunits, SMARCA4 (603254) and SMARCC1 (601732).
Using courtship conditioning assays, Nixon et al. (2019) found that targeted knockdown of the SMARCD1 ortholog (Bap60) in Drosophila postmitotic memory-forming neurons of the mushroom body (MB), the center for learning and memory in the fly brain, resulted in impaired memory formation. Gene expression and ontology analysis of MB cells with RNAi knockdown of Bap60 showed dysregulation of muscle- and neuron-related genes, particularly at the juvenile stage of development. These findings suggested a role for SMARCD1 in context-dependent activation during neurodevelopment, with a possible role in the establishment of experience-dependent synaptic transmission.
In a 7-year-old girl (patient 1) with Coffin-Siris syndrome-11 (CSS11; 618779), Nixon et al. (2019) identified a heterozygous c.990C-G transversion (c.990C-G, NM_003076.4) in the SMARCD1 gene, resulting in an asp330-to-glu (D330E) substitution at a highly conserved residue in the SWIB domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the mother; paternal DNA was not available. In vitro functional expression studies using expression constructs showed that the D330E protein was expressed at normal levels and did not abolish the interaction of mutant SMARCD1 with at least 2 other complex subunits.
In an 11-year-old boy (patient 2) with Coffin-Siris syndrome-11 (CSS11; 618779), Nixon et al. (2019) identified a de novo heterozygous c.1336A-G transition (c.1336A-G, NM_003076.4) in the SMARCD1 gene, resulting in an arg446-to-gly (R446G) substitution at a conserved residue in the C-terminal domain. The mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 6-year-old boy (patient 3) with Coffin-Siris syndrome-11 (CSS11; 618779), Nixon et al. (2019) identified a de novo heterozygous c.1457G-A transition (c.1457G-A, NM_003076.4) in the SMARCD1 gene, resulting in a trp486-to-ter (W486X) substitution in the C-terminal domain. The mutation was predicted to escape nonsense-mediated mRNA decay, although functional studies of the variant and studies of patient cells were not performed. The mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies using expression constructs showed that the W486X protein was expressed at normal levels and did not abolish the interaction of mutant SMARCD1 with at least 2 other complex subunits.
In a 3-year-old boy (patient 4) with Coffin-Siris syndrome-11 (CSS11; 618779), Nixon et al. (2019) identified a de novo heterozygous c.1483T-C transition (c.1483T-C, NM_003076.4) in the SMARCD1 gene, resulting in a phe495-to-leu (F495L) substitution at a conserved residue in the C-terminal domain. The mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies using expression constructs showed that the F495L protein was expressed at normal levels and did not abolish the interaction of mutant SMARCD1 with at least 2 other complex subunits.
In a 27-month-old girl (patient 5) with Coffin-Siris syndrome-11 (CSS11; 618779), Nixon et al. (2019) identified a de novo heterozygous c.1507C-T transition (c.1507C-T, NM_003076.4) in the SMARCD1 gene, resulting in an arg503-to-ter (R503X) substitution in the C-terminal domain. The mutation was predicted to escape nonsense-mediated mRNA decay, although functional studies of the variant and studies of patient cells were not performed.
Nixon, K. C. J., Rousseau, J., Stone, M. H., Sarikahya, M., Ehresmann, S., Mizuno, S., Matsumoto, N., Miyake, N., DDD Study, Baralle, D., McKee, S., Izumi, K., Ritter, A. L., Heide, S., Heron, D., Depienne, C., Titheradge, H., Kramer, J. M., Campeau, P. M. A syndromic neurodevelopmental disorder caused by mutations in SMARCD1, a core SWI/SNF subunit needed for context-dependent neuronal gene regulation in flies. Am. J. Hum. Genet. 104: 596-610, 2019. [PubMed: 30879640] [Full Text: https://doi.org/10.1016/j.ajhg.2019.02.001]
Ring, H. Z., Vameghi-Meyers, V., Wang, W., Crabtree, G. R., Francke, U. Five SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome. Genomics 51: 140-143, 1998. [PubMed: 9693044] [Full Text: https://doi.org/10.1006/geno.1998.5343]
Wang, W., Xue, Y., Zhou, S., Kuo, A., Cairns, B. R., Crabtree, G. R. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 10: 2117-2130, 1996. [PubMed: 8804307] [Full Text: https://doi.org/10.1101/gad.10.17.2117]