Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCD2
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38): 17:63,832,081-63,842,685 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.3 | Specific granule deficiency 2 | 617475 | Autosomal recessive | 3 |
The SMARCD2 gene encodes a component SWI/SNF chromatin remodeling complex in hematopoietic stem cells and other hematopoietic cells, where it plays a role in the regulation of transcription factors during hematopoietic differentiation, particularly of myeloid cells (summary by Witzel et al., 2017).
See also BAF155 (601732) and BAF170 (601734), other subunits in this complex.
Chromatin is actively remodeled during development. Chromatin remodeling of certain genes appears to precede their transcriptional activation. In yeast, the multisubunit SWI/SNF complex is thought to be responsible for chromatin remodeling. Wang et al. (1996) isolated an analogous SWI/SNF complex from the human YT cell line. 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) cloned the BAF60b subunit based on its homology with BAF60a (601735). BAF60b encodes a polypeptide of 475 amino acids and is homologous to the yeast SWP73 gene, a component of the yeast SWI/SNF chromatin remodeling complex. The human genes BAF60a, BAF60b, and BAF60c (601737) are highly homologous.
By PCR of a somatic cell hybrid panel and radiation hybrid analysis, Ring et al. (1998) mapped the SMARCD2 gene to chromosome 17q23-q24.
In studies in human and mouse hematopoietic cells, as well as Smarcd2-null mouse embryonic cells, Witzel et al. (2017) demonstrated that SWI/SNF complexes containing SMARCD2 have specific roles in various stages of differentiation of myeloid-erythroid progenitor cells and granulopoiesis. Gene expression studies suggested that SMARCD2 acted as a transcriptional repressor in immature progenitor cells and as an activator at more differentiated stages of granulopoiesis. In addition, SMARCD2 mediated the expression of neutrophil granule proteins in later stages of neutrophil development via direct interaction with CEBPE (600749), a myeloid transcription factor that controls expression of specific granule genes in neutrophils. Although lack of SMARCD2 did not affect the expression of CEBPE, its absence impaired recruitment of CEBPE to transcription start sites and open chromatin, thus interfering with expression of CEBPE-dependent genes. Witzel et al. (2017) concluded that SMARCD2 has a direct role in chromatin remodeling in myeloid cells, which mediates downstream gene expression.
In studies of mouse gene deletion mutants, Priam et al. (2017) found that Smarcd2 function is mediated by the coiled-coil-1 (C1) and SWIB domains, which are necessary for Cebpe and SWI/SNF recruitment to the promoters of secondary granule genes as well as for their transcriptional activation.
In 4 patients from 3 unrelated consanguineous families with specific granule deficiency-2 (SGD2; 617475), Witzel et al. (2017) identified homozygous frameshift loss-of-function mutations in the SMARCD2 gene (601736.0001-601736.0003). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Immunoblot analysis showed absence of the SMARCD2 protein in patient-derived cells. Expression of the truncated isoforms in 293T cells showed that they were unable to coprecipitate with other SMARCD proteins in the SWI/SMF chromatin remodeling complex, indicating a loss of function. Studies in zebrafish and mice (see ANIMAL MODEL) showed that Smarcd2 orchestrates hematopoietic stem cell differentiation, particularly for the myeloid line. Loss of SMARCD2 function interfered with proper myeloid cell development and expression of genes involved in neutrophil granule formation.
In an 11-year-old girl, born of consanguineous Turkish parents, with SGD2, Yucel et al. (2021) identified a homozygous frameshift mutation in the SMARCD2 gene (601736.0004). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a girl, born of consanguineous parents, with SGD2, Schim van der Loeff et al. (2021) identified a homozygous splice site mutation in the SMARCD2 gene (601736.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed 3 different truncated SMARCD2 mRNA transcripts resulting from the splicing defect. Patient neutrophils were phenotypically immature and showed impaired oxidative burst activity in response to certain stimulants; chemotaxis was also abnormal. In vitro studies showed defective killing of Staphylococcus aureus. Patient CD34+ cells showed impaired expansion and differentiation toward the neutrophil lineage compared to controls. These findings suggested a severe and specific abnormality of the myeloid compartment.
In a male infant, born of consanguineous Turkish parents, with SGD2, Kihtir et al. (2022) identified a homozygous nonsense mutation in the SMARCD2 gene (Q171X; 601736.0005). The mutation was found by whole-exome sequencing; each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed.
Witzel et al. (2017) found that morpholino knockdown of the smarcd2 ortholog in zebrafish embryos resulted in a significant reduction in the number of neutrophil granulocytes compared to controls. There were no marked effects on granulocyte morphology, no qualitative differences in erythrocytes, and no quantitative differences in macrophages or thrombocytes. CRISPR/Cas9 genome editing of the smarcd2 ortholog to create a frameshift also resulted in reduced granulocyte abundance. The findings showed the lineage-specific effects of smarcd2.
Witzel et al. (2017) found that Smardc2-null mouse embryos died late during fetal development, and fetal liver cells from these mice showed a reduction in granulocyte/macrophage progenitors as well as reduced neutrophil granulocytes and monocytes compared to controls. Hematopoietic stem cells showed reduced colony-forming unit size and numbers and maturation arrest, and did not differentiate in response to cytokines. Smardc2-null embryos also showed a maturation arrest of erythropoietic cells, with extensive anisocytosis of erythrocytes, multinucleated cells, perturbed mitosis, and increased apoptosis. Gene expression profiling of wildtype and mutant cells showed differential expression of genes involved in granulopoiesis and in megakaryocyte-erythrocyte progenitors, with evidence suggesting variable roles for Smardc2 at different stages during granulopoiesis.
Priam et al. (2017) found that Smarcd2-null mice died within 26 hours of birth, had decreased weight and reduction of adipose tissue reminiscent of a lipodystrophy, and had decreased hepatic glycogen content, suggesting a defect in neonatal energy homeostasis. Targeted deletion of Smarcd2 in the adult hematopoietic system resulted in a block at the myelocyte/metamyelocyte stage of maturation with dysplastic features leading to premature death. Blood cell counts and bone marrow samples showed a near complete absence of segmented neutrophils and eosinophils in the animals, although other lineages were present. Mutant mice also developed progressive lung disease associated with pulmonary infiltration by nonlymphoid immature dysplastic cells. Gene expression studies of bone marrow cells derived from mutant mice showed significant downregulation of secondary and tertiary neutrophilic granule genes. The granulocytic differentiation defect could not be rescued by expression of Smarcd1 (601735) in cells derived from mutant mice.
In a boy, born of consanguineous Pakistani parents, with specific granule deficiency-2 (SGD2; 617475), Witzel et al. (2017) identified a homozygous G-to-A transition (c.1181+1G-A, NM_001098426.1) in intron 9 of the SMARCD2 gene, causing a splice site mutation and the production of 3 aberrant transcripts that resulted in frameshifts and premature termination: Ile362CysfsTer3 (given as Ile362CysfsTer2 in Figure 3), Ser394ArgfsTer1, and Ile362ValfsTer85. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Immunoblot analysis showed absence of the SMARCD2 protein in patient-derived cells. Expression of 2 of the truncated isoforms in 293T cells showed that neither was able to coprecipitate with other SMARCD proteins, indicating a loss of function.
In a girl, born of consanguineous parents, with SGD2, Schim van der Loeff et al. (2021) identified a homozygous c.1181+1G-A transition in the SMARCD2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed 3 different truncated SMARCD2 mRNA transcripts resulting from the splicing defect. Patient neutrophils were phenotypically immature and showed impaired oxidative burst activity in response to certain stimulants; chemotaxis was also abnormal. In vitro studies showed defective killing of Staphylococcus aureus. Patient CD34+ cells showed impaired expansion and differentiation toward the neutrophil lineage compared to controls. These findings suggested a severe and specific abnormality of the myeloid compartment.
In 2 sibs, born of consanguineous Pakistani parents, with specific granule deficiency-2 (SGD2; 617475), Witzel et al. (2017) identified a homozygous 25-bp duplication (c.414_438dup, NM_001098426.1) in the SMARCD2 gene, resulting in a frameshift and premature termination (Gln147GlufsTer5, given as Gln147GlufsTer4 in Figure 3). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Immunoblot analysis showed absence of the SMARCD2 protein in patient-derived cells. Expression of the truncated isoform in 293T cells showed that it was unable to coprecipitate with other SMARCD proteins, indicating a loss of function.
In a boy, born of consanguineous Lebanese parents, with specific granule deficiency-2 (SGD2; 617475), Witzel et al. (2017) identified a homozygous T-to-C transition (c.401+2T-C, NM_001098426.1), in intron 2 of the SMARCD2 gene, resulting in a splice site alteration, a frameshift, and premature termination (Arg73ValfsTer8). The mutation segregated with the disorder in the family. Immunoblot analysis showed absence of the SMARCD2 protein in patient-derived cells. Expression of the truncated isoform in 293T cells showed that it was unable to coprecipitate with other SMARCD proteins, indicating a loss of function.
In an 11-year-old girl, born of consanguineous Turkish parents, with specific granule deficiency-2 (SGD2; 617475), Yucel et al. (2021) identified a homozygous 1-bp deletion (c.93del, NM_001098426.2) in exon 1 of the SMARCD2 gene, resulting in a frameshift and premature termination (Ala32ArgfsTer80) close to the N-terminal. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a male infant, born of consanguineous Turkish parents, with specific granule deficiency-2 (SGD2; 617475), Kihtir et al. (2022) identified a homozygous c.511C-T transition in the SMARCD2 gene, resulting in a gln171-to-ter (Q171X) substitution. The mutation was found by whole-exome sequencing; each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed.
Kihtir, Z., Celik, K., Tayfun Kupesiz, F., Kupesiz, O. A., Kocacik Uygun, D. F., Arayici, S., Ongun, H., Acarbulut, I., Saglam, C., Ceylaner, G., Bingol, A. Specific granule deficiency due to novel homozygote SMARCD2 variant. Pediat. Allergy Immun. Pulmonol. 35: 43-46, 2022. [PubMed: 35320004] [Full Text: https://doi.org/10.1089/ped.2021.0070]
Priam, P., Krasteva, V., Rousseau, P., D'Angelo, G., Gaboury, L., Sauvageau, G., Lessard, J. A. SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBP-epsilon dependent mechanism. Nature Genet. 49: 753-764, 2017. [PubMed: 28369034] [Full Text: https://doi.org/10.1038/ng.3812]
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]
Schim van der Loeff, I., Sprenkeler, E. G. G., Tool, A. T. J., Abinun, M., Grainger, A., Engelhardt, K. R., van Houdt, M., Janssen, H., Kuijpers, T. W., Hambleton, S. Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2. J. Allergy Clin. Immun. 147: 2381-2385, 2021. [PubMed: 33279574] [Full Text: https://doi.org/10.1016/j.jaci.2020.11.025]
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]
Witzel, M., Petersheim, D., Fan, Y., Bahrami, E., Racek, T., Rohlfs, M., Puchalka, J., Mertes, C., Gagneur, J., Ziegenhain, C., Enard, W., Stray-Pedersen, A., and 12 others. Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes. Nature Genet. 49: 742-752, 2017. [PubMed: 28369036] [Full Text: https://doi.org/10.1038/ng.3833]
Yucel, E., Karakus, I. S., Krolo, A., Kiykim, A., Heredia, R. J., Tamay, Z., Cipe, F. E., Karakoc-Aydiner, E., Ozen, A., Karaman, S., Boztug, K., Baris, S. Novel frameshift autosomal recessive loss-of-function mutation in SMARCD2 encoding a chromatin remodeling factor mediates granulopoiesis. J. Clin. Immun. 41: 59-65, 2021. [PubMed: 33025377] [Full Text: https://doi.org/10.1007/s10875-020-00878-4]