Alternative titles; symbols
HGNC Approved Gene Symbol: SNTA1
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:33,407,957-33,443,763 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.21 | Long QT syndrome 12 | 612955 | Autosomal dominant | 3 |
Syntrophin is a peripheral membrane protein of relative mass approximately 58,000 that was first identified in the postsynaptic membrane of Torpedo electric organ and subsequently shown to be present in many mammalian tissues. Interest in syntrophin came first from its location at the neuromuscular junction and later from the demonstration that it is directly associated with dystrophin (310200). A potential role for the dystrophin-associated proteins in agrin-stimulated nicotinic acetylcholine receptor clustering has implicated syntrophin in the process of synaptogenesis. At least 3 different but highly conserved syntrophin isoforms are encoded by distinct genes: alpha-1, beta-1 (600026), and beta-2 (600027). Each has approximately 50% amino acid identity with the other 2. These 3 syntrophins can be separated into 2 classes based on isoelectric points: the acidic isoform, alpha-1-syntrophin (pI = 6.7), and the 2 basic forms, beta-1 and beta-2 (pI = 9.0).
Adams et al. (1995) cloned and characterized the mouse alpha-1- and beta-2-syntrophin genes. Analysis of the amino acid sequence revealed the presence of 4 conserved domains. The C-terminal 56 amino acids are highly conserved and constitute a syntrophin-unique domain. Two pleckstrin (173570) homology domains are located in the N-terminal end of the protein. The first pleckstrin homology domain is interrupted by a domain homologous to repeated sequences originally found in the Drosophila discs-large protein (601014).
Ahn et al. (1996) showed that whereas beta-1-syntrophin and beta-2-syntrophin are expressed widely, although in a distinct pattern of relative abundance, alpha-1-syntrophin is most abundant in heart and skeletal muscle, and less so in other tissues.
Fernandez-Larrea et al. (1999) used the 2-hybrid screen to identify pro-TGF-alpha (190170) cytoplasmic domain-binding proteins, which they referred to as TACIPs (pro-TGF-alpha cytoplasmic domain-interacting proteins), involved in the trafficking of pro-TGF-alpha. They cloned 2 such proteins, TACIP1 and TACIP18, both of which showed a lack of interaction with a pro-TGF-alpha C-terminal mutant that does not reach the cell surface. TACIP1 and TACIP18 are identical to the PDZ proteins alpha-1-syntrophin and syntenin (602217), respectively. PDZ domains are known to bind to the C terminus of a variety of transmembrane proteins. Accordingly, Fernandez-Larrea et al. (1999) demonstrated that the PDZ domains of TACIP1 and TACIP18 are responsible for the interaction with the cytoplasmic domain of pro-TGF-alpha. Analysis of a panel of pro-TGF-alpha C-terminal mutants showed that mutations that prevented the binding to TACIP1, but not to TACIP18, did not disrupt the transport of pro-TGF-alpha to the cell surface in vivo.
Adams et al. (1995) determined that the mouse Snta1 gene spans more than 24 kb and contains 8 exons. Primer extension analysis revealed 2 transcription initiation sites. The sequence immediately 5-prime of the transcription start sites lacks a TATA box but is GC-rich and has multiple putative Sp1 (189906)-binding sites.
Adams et al. (1995) mapped the SNTA1 gene to mouse chromosome 2 by study of an interspecific backcross panel and to human chromosome 20 by study of a hamster/human somatic cell hybrid panel. By PCR analysis of somatic cell hybrids and fluorescence in situ hybridization, Ahn et al. (1996) mapped the SNTA1 gene to chromosome 20q11.2.
Using various methods, Lanciotti et al. (2012) found that MLC1 (605908), TRPV4 (605427), HEPACAM (611642), syntrophin, caveolin-1 (CAV1; 601047), Kir4.1 (KCNJ10; 602208), and AQP4 (600308) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress.
Ueda et al. (2008) analyzed the SNTA1 gene in 50 unrelated patients with long QT syndrome (LQTS; see LQT12, 612955) who were negative for mutations in the 11 known LQTS genes and identified a heterozygous missense mutation in 1 patient (A390V; 601017.0001). Using a GST-fusion protein of the C terminus of SCN5A (600163) in HEK293 cells, the authors demonstrated that SNTA1 interacts with SCN5A, nNOS (see 163731), and PMCA4b (see ATP2B4, 108732); in contrast, mutant SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. Mutant SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared to wildtype, and the increase was partially inhibited by NOS blockers; expression of mutant SNTA1 in cardiac myocytes also increased late sodium current. Ueda et al. (2008) concluded that the A390V mutation disrupts binding with PMCA4b, releases inhibition of nNOS, causes S-nitrosylation of SCN5A, and is associated with increased late sodium current, which is the characteristic biophysical dysfunction in sodium channel-mediated LQTS (see LQT3, 603830).
In 3 unrelated patients with long QT syndrome, Wu et al. (2008) identified heterozygosity for a missense mutation in the SNTA1 gene (A257G; 601017.0002). Electrophysiologic analysis suggested that A257G mutant channels exhibit a gain of function through 3 mechanisms: increase of channel availability by leftward shift of activation kinetics, delay of current decay, and increase in current density. In 1 family, affected individuals also carried a variant of unknown significance in the KCNQ1 gene (607542), IVS7+5G-A.
Hosaka et al. (2002) developed Snta1-null mice and found that they had no gross histologic changes. There were, however, important differences in muscle regeneration following injection of cardiotoxin into the tibialis anterior muscle. Initially, regeneration of wildtype and Snta1-null muscles was indistinguishable. After 2 weeks, though, the Snta1-null muscles were hypertrophied and showed extensive fiber splitting, deranged neuromuscular junctions, and reduced contractile force. Snta1-null mice also showed impaired exercise endurance in the early phase of regeneration. Hosaka et al. (2002) noted that these abnormalities are typically observed in the early stages of Duchenne muscular dystrophy (310200) and suggested that lack of Snta1 may be partly responsible for the pathologic changes.
In a man with long QT syndrome (LQT12; 612955), Ueda et al. (2008) identified heterozygosity for a C-to-T transition in the SNTA1 gene, resulting in an ala390-to-val (A390V) substitution at a highly conserved residue. The patient, who had a corrected QT interval of 529 ms on electrocardiography, had been diagnosed with LQTS at 18 years of age after syncopal episodes but had no other symptoms of cardiac or skeletal muscle disease. Mutant SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared to wildtype, and the increase was partially inhibited by NOS blockers; expression of mutant SNTA1 in cardiac myocytes also increased late sodium current. The mutation was not found in 600 reference alleles.
In 3 unrelated patients with long QT syndrome (LQT12; 612955), Wu et al. (2008) identified heterozygosity for an ala257-to-gly (A257G) substitution at a highly conserved residue in the SNTA1 protein. The mutation was not detected in 400 ethnically matched alleles. In 2 women, the change arose de novo, as it was not present in their unaffected parents, who had normal electrocardiograms. The third patient was a 17-year-old boy, whose sister, mother, maternal uncle, and maternal grandmother were also affected and heterozygous for the mutation; affected members of this family were also heterozygous for a variant of unknown significance in the KCNQ1 gene (607542), IVS7+5G-A. Electrophysiologic analysis in transfected HEK293 cells suggested that A257G mutant channels exhibit a gain of function through 3 mechanisms: increase of channel availability by leftward shift of activation kinetics, delay of current decay, and increase in current density.
Adams, M. E., Dwyer, T. M., Dowler, L. L., White, R. A., Froehner, S. C. Mouse alpha-1- and beta-2-syntrophin gene structure, chromosome localization, and homology with a discs large domain. J. Biol. Chem. 270: 25859-25865, 1995. [PubMed: 7592771] [Full Text: https://doi.org/10.1074/jbc.270.43.25859]
Ahn, A. H., Freener, C. A., Gussoni, E., Yoshida, M., Ozawa, E., Kunkel, L. M. The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives. J. Biol. Chem. 271: 2724-2730, 1996. [PubMed: 8576247] [Full Text: https://doi.org/10.1074/jbc.271.5.2724]
Fernandez-Larrea, J., Merlos-Suarez, A., Urena, J. M., Baselga, J., Arribas, J. A role for a PDZ protein in the early secretory pathway for the targeting of proTGF-alpha to the cell surface. Molec. Cell 3: 423-433, 1999. [PubMed: 10230395] [Full Text: https://doi.org/10.1016/s1097-2765(00)80470-0]
Hosaka, Y., Yokota, T., Miyagoe-Suzuki, Y., Yuasa, K., Imamura, M., Matsuda, R., Ikemoto, T., Kameya, S., Takeda, S. Alpha-1-syntrophin-deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration. J. Cell Biol. 158: 1097-1107, 2002. [PubMed: 12221071] [Full Text: https://doi.org/10.1083/jcb.200204076]
Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E. Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations. Hum. Molec. Genet. 21: 2166-2180, 2012. [PubMed: 22328087] [Full Text: https://doi.org/10.1093/hmg/dds032]
Ueda, K., Valdivia, C., Medeiros-Domingo, A., Tester, D. J., Vatta, M., Farrugia, G., Ackerman, M. J., Makielski, J. C. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc. Nat. Acad. Sci. 105: 9355-9360, 2008. [PubMed: 18591664] [Full Text: https://doi.org/10.1073/pnas.0801294105]
Wu, G., Ai, T., Kim, J. J., Mohapatra, B., Xi, Y., Li, Z., Abbasi, A., Purevjav, E., Samani, K., Ackerman, M. J., Qi, M., Moss, A. J., Shimizu, W., Towbin, J. A., Cheng, J., Vatta, M. Alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ. Arrhythm. Electrophysiol. 1: 193-201, 2008. [PubMed: 19684871] [Full Text: https://doi.org/10.1161/CIRCEP.108.769224]