HGNC Approved Gene Symbol: SVIL
Cytogenetic location: 10p11.23 Genomic coordinates (GRCh38) : 10:29,457,338-29,736,936 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p11.23 | Myofibrillar myopathy 10 | 619040 | Autosomal recessive | 3 |
The SVIL gene encodes supervillin, which belongs to the villin/gelsolin superfamily of actin-binding proteins involved in many cellular processes. One of the SVIL isoforms is expressed in skeletal and cardiac muscle tissue where it plays a role in both muscle fiber structure and signaling (summary by Hedberg-Oldfors et al., 2020).
Supervillin is tightly associated with both actin filaments and plasma membranes, suggesting that it forms a link between the actin cytoskeleton and the membrane (Pope et al., 1998).
Pope et al. (1998) used PCR with primers based on bovine sequence to clone human supervillin, a 205-kD F-actin-binding protein. The human gene encodes a 1,788-amino acid polypeptide that contains 3 predicted nuclear localization signals, several consensus phosphorylation sites, 1 ATP/GTP-binding motif, 1 potential RNP-binding site, and 3 potential actin-binding sites. The region containing the actin-binding sites is similar to the 'headpiece' of villin (193040). Dot blots showed that many tissues express supervillin, with the highest expression in muscle tissues. Northern blot analysis revealed a 7.5-kb mRNA that is abundant in some human cancer cell lines. Southern blot analysis revealed that supervillin is a single-copy gene.
Activation of androgen receptor (AR; 313700) via androgen in muscle cells is closely linked to their growth and differentiation. Ting et al. (2002) cloned and characterized supervillin as an AR coregulator from a skeletal muscle cDNA library. They identified a domain within supervillin (amino acids 594 to 1,268) that could interact with the AR N terminus and DNA-binding domain-ligand-binding domain in a ligand-enhanced manner. Subcellular colocalization studies with fluorescence staining indicated that supervillin colocalized with AR in the presence of 5-alpha-dihydrotestosterone in COS-1 cells. Furthermore, supervillin could enhance expression of the endogenous AR target gene p27(KIP1) (600778) in prostate cells. Thus, supervillin is an AR coregulator that can enhance AR transactivation in muscle and other cells.
The most prominently expressed SVIL isoform in cardiac and skeletal muscle is SV2, which has a molecular mass of 250 kD. The protein localizes to the ends of differentiating myotubes and binds to structural proteins such as F-actin (ACTA1; 102610), vinculin (VCL; 193065), and non-muscle myosin II (see, e.g., MYH9, 160775). This suggests that SVIL coordinates Z-line attachment to sarcomeres. SVIL may also play a role in signaling (summary by Hedberg-Oldfors et al., 2020).
Pope et al. (1998) used fluorescence in situ hybridization to map the supervillin gene to chromosome 10p11.2
In 4 patients from 2 unrelated consanguineous families with myofibrillar myopathy-10 (MFM10; 619040), Hedberg-Oldfors et al. (2020) identified homozygous loss-of-function mutations in the SVIL gene (604126.0001 and 604126.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies of the variants were not performed, but patient skeletal muscle tissue showed decreased SVIL mRNA and protein levels compared to controls. Skeletal muscle biopsies showed subsarcolemmal accumulation of degraded myofibrils, pleomorphic material, and autophagy-associated organelles with lipoprotein deposits including lipofuscin. Rare nemaline rods were observed. Detailed immunochemical studies identified abnormal aggregation of CAV3 (601253), dystrophin (DMD; 300377), dysferlin (603009), desmin (125660), and alpha-sarcoglycan (SGCA; 600119). Other identified proteins included p62 (SQSTM1; 601530), and LC3 (601242), markers of autophagocytosis. The authors postulated that the loss of SVIL causes a structural myopathy with myofibrillar disintegration and disrupted autophagy.
In 2 brothers, born of consanguineous Lebanese parents (family 1), with myofibrillar myopathy-10 (MFM10; 619040), Hedberg-Oldfors et al. (2020) identified a homozygous c.4812C-A transversion (c.4812C-A, NM_021738.2) in exon 27 of the SVIL gene, resulting in a tyr1604-to-ter (Y1604X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ExAC, gnomAD, 1000 Genomes Project, dbSNP (build 151), or ESP databases. Patient skeletal muscle samples showed decreased levels of SVIL transcript compared to controls, suggesting that most of the mutant transcripts were subjected to nonsense-mediated mRNA decay. The findings were consistent with a loss-of-function effect. In addition to muscle fatigue and pain, the patients developed cardiac involvement with left ventricular hypertrophy and EKG abnormalities.
In 2 brothers, born of consanguineous Turkish parents (family 2) with myofibrillar myopathy-10 (MFM10; 619040), Hedberg-Oldfors et al. (2020) identified a homozygous 2-bp deletion (c.3578_3579delTG, NM_021738.2) in exon 18 of the SVIL gene, resulting in a frameshift and premature termination (Val1193GlufsTer46). The mutation, which was found by exome sequencing, segregated with the disorder in the family; it was not present in public databases. Western blot analysis of patient skeletal muscle tissue showed complete absence of the full-length SVIL protein. The findings were consistent with a loss-of-function effect. The patients had slowly progressive muscle rigidity and contractures; the only had subclinical cardiac involvement.
Hedberg-Oldfors, C., Meyer, R., Nolte, K., Abdul Rahim, Y., Lindberg, C., Karason, K., Thuestad, I. J., Visuttijai, K., Geijer, M., Begemann, M., Kraft, F., Lausberg, E., and 12 others. Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles. Brain 143: 2406-2420, 2020. Note: Erratum: Brain 144: e34, 2021. [PubMed: 32779703] [Full Text: https://doi.org/10.1093/brain/awaa206]
Pope, R. K., Pestonjamasp, K. N., Smith, K. P., Wulfkuhle, J. D., Strassel, C. P., Lawrence, J. B., Luna, E. J. Cloning, characterization, and chromosomal localization of human supervillin (SVIL). Genomics 52: 342-351, 1998. [PubMed: 9867483] [Full Text: https://doi.org/10.1006/geno.1998.5466]
Ting, H.-J., Yeh, S., Nishimura, K., Chang, C. Supervillin associates with androgen receptor and modulates its transcriptional activity. Proc. Nat. Acad. Sci. 99: 661-666, 2002. [PubMed: 11792840] [Full Text: https://doi.org/10.1073/pnas.022469899]