HGNC Approved Gene Symbol: STAC3
SNOMEDCT: 723439002;
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38) : 12:57,243,458-57,251,187 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Congenital myopathy 13 | 255995 | Autosomal recessive | 3 |
STAC3 is a component of the excitation-contraction coupling machinery of muscles (Horstick et al., 2013).
Using a zebrafish genetic screen, Horstick et al. (2013) created a locomotor mutant with decreased excitation-contraction (EC) coupling that mapped to the stac3 gene. The autosomal recessive mutants exhibited a variety of defective motor behaviors during early development and died as larvae. Their nervous systems appeared to be normal but muscles in the mutant animals contracted much less following depolarization than in wildtype zebrafish. Overall myofiber morphology appeared normal in the mutant larvae, but Ca(2+) transients were greatly reduced as expected for a defect in EC coupling. An antibody against stac3 detected an approximately 49-kD protein in normal zebrafish, consistent with the predicted 334-amino acid normal protein, but no protein was seen in the homozygous mutants. The antibody was also used to detect stac3 protein in skeletal muscle triads where it colocalized with DHPR alpha-1 (CACNA1C; 114205) and presumably with RYR1 (180901), a gene that is defective in malignant hyperthermia. Horstick et al. (2013) were able to rescue the mutant using the wildtype gene, and the rescued larvae had restored calcium transients. The authors concluded that stac3 is a component of the triadic complex of proteins.
The STAC3 gene maps to chromosome 12q13-q14 (Horstick et al., 2013).
Horstick et al. (2013) sequenced the coding regions of the STAC3 gene in a cohort of 5 Native American families with congenital myopathy-13 (CMYO13; 255995), also known as Native American myopathy (NAM), that included 5 affected and 13 unaffected individuals. All affected individuals were homozygous for a missense mutation (W284S; 615521.0001), whereas all obligate carriers were heterozygous for the mutation.
In a 19-year-old man, born of unrelated Turkish parents, with CMYO13, Grzybowski et al. (2017) identified compound heterozygous mutations in the STAC3 gene (615521.0002 and 615521.0003). The mutations, which were identified by next-generation sequencing of a panel of genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
In 2 sibs, born of consanguineous parents from Qatar, with CMYO13, Telegrafi et al. (2017) identified a homozygous W284S mutation. Two sibs from Puerto Rico with the same phenotype were found to be compound heterozygous for the W284S mutation and a 4-bp deletion (c.763_766delCTCT; 615521.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the report demonstrated that the W284S mutation is not restricted to the Native American population.
In 17 patients from 11 apparently unrelated families with Bailey-Bloch congenital myopathy (CMYO13), Zaharieva et al. (2018) identified homozygosity for the W84S mutation in the STAC3 gene; in an unrelated patient (PN5), they identified compound heterozygosity for the W84S mutation and a splice site mutation (615521.0005). The mutations, which were identified by whole-exome sequencing or targeted panel sequencing of known congenital myopathy genes, were confirmed by Sanger sequencing. The mutations segregated with the phenotype in all of the families, which were of African, Middle Eastern, Afro-Caribbean, Comorian, and South American descent.
In a cohort of 5 families with congenital myopathy-13 (CMYO13; 255995), also known as Native American myopathy and Bailey-Bloch congenital myopathy, Horstick et al. (2013) sequenced the coding regions of the STAC3 gene and identified homozygosity for a c.1046G-C transversion (c.1046G-C, NM_145064) in exon 10, resulting in a trp284-to-ser (W284S; 615521.0001), in all 5 affected individuals. Among 13 unaffected individuals, all obligate carriers were heterozygous for the mutation. The mutation was not found in 3 unaffected, unrelated Lumbee individuals, in 13 Caucasian control individuals, or in the 1000 Genomes Project database. Horstick et al. (2013) created zebrafish with the W284S mutation, which exhibited decreased Ca(2+) transients. Conversely, expression of the normal human STAC3 gene in mutant fish rescued their phenotype.
In 2 sibs, born of consanguineous parents from Qatar, with CMYO13, Telegrafi et al. (2017) identified a homozygous W284S mutation, which they referred to as resulting from a c.851G-C transversion (NM_145064.2). These authors noted that the mutation occurs at a highly conserved residue in the first SH3 domain. Two sibs from Puerto Rico with the same phenotype were found to be compound heterozygous for the W284S mutation and a 4-bp deletion (c.763_766delCTCT; 615521.0004), predicted to result in a frameshift and premature termination (Leu255IlefsTer58). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The W284S mutation was filtered against the dbSNP, 1000 Genomes Project, and Exome Variant Server databases; the mutation was found in heterozygous state in 13 of 121,350 alleles in the ExAC database. The 4-bp deletion was not found in the dbSNP database, but was found in heterozygous state in 2 of 121,242 alleles in the ExAC database. Functional studies of the variants and studies of patient cells were not performed, but the report demonstrated that the W284S mutation is not restricted to the Native American population.
In 17 patients with CMYO13 from 11 apparently unrelated families of non-Native American descent, Zaharieva et al. (2018) identified homozygosity for the W84S mutation in the STAC3 gene. In another patient (PN5), of Afro-Caribbean descent, they identified compound heterozygosity for the W84S substitution and a splice site mutation (c.997-1G-T; 615521.0005) in STAC3, which abolished the acceptor splice site of exon 12, leading to activation of a cryptic acceptor site within exon 12. cDNA sequencing confirmed a 12-bp in-frame deletion, which eliminated 4 amino acids from the second SH3 domain. The mutations segregated with the disorder in all of the families.
In a 19-year-old man, born of unrelated Turkish parents, with congenital myopathy-13 (CMYO13; 255995), Grzybowski et al. (2017) identified compound heterozygous mutations in the STAC3 gene: a c.862A-T transversion (c.862A-T, NM_145064.2), resulting in a lys288-to-ter (K288X) substitution in the first SH3 domain, and an A-to-T transversion in intron 4 (c.432+4A-T; 615521.0003), which was demonstrated to result in abnormal splicing and the production of several abnormal transcripts. The mutations, which were identified by next-generation sequencing of a panel of genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
For discussion of the A-to-T transversion in intron 4 of the STAC3 gene (c.432+4A-T, NM_145064.2) that was found in compound heterozygous state in a patient with congenital myopathy-13 (CMYO13; 255995) by Grzybowski et al. (2017), see 615521.0002.
For discussion of the 4-bp deletion (c.763_766delCTCT, NM_145064.2) in the STAC3 gene, predicted to result in a frameshift and premature termination (Leu255Il3Ter58), that was found in compound heterozygous state in 2 sibs with congenital myopathy-13 (CMYO13; 255995) by Telegrafi et al. (2017), see 615521.0001.
For discussion of the splice site variant (c.997-G-T, NM_145064.2) in the STAC3 gene that was found in compound heterozygous state in a patient (PN5) of Afro-Caribbean descent with congenital myopathy-13 (CMYO13; 255995) by Zaharieva et al. (2018), see 615521.0001.
Grzybowski, N., Schanzer, A., Pepler, A., Heller, C., Neubauer, B. A., Hahn, A. Novel STAC3 mutations in the first non-Native American patient with Native American myopathy. Neuropediatrics 48: 451-455, 2017. [PubMed: 28411587] [Full Text: https://doi.org/10.1055/s-0037-1601868]
Horstick, E. J., Linsley, J. W., Dowling, J. J., Hauser, M. A., McDonald, K. K., Ashley-Koch, A., Saint-Amant, L., Satish, A., Cui, W. W., Zhou, W., Sprague, S. M., Stamm, D. S., Powell, C. M., Speer, M. C., Franzini-Armstrong, C., Hirata, H., Kuwada, J. Y. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nature Commun. 4: 1952, 2013. Note: Electronic Article. [PubMed: 23736855] [Full Text: https://doi.org/10.1038/ncomms2952]
Telegrafi, A., Webb, B. D., Robbins, S. M., Speck-Martins, C. E., FitzPatrick, D., Fleming, L., Redett, R., Dufke, A., Houge, G., van Harssel, J. J. T., Verloes, A., Robles, A., Manoli, I., Engle, E. C., Moebius Syndrome Research Consortium, Jabs, E. W., Valle, D., Carey, J., Hoover-Fong, J. E., Sobreira, N. L. M. Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. Am. J. Med. Genet. 173A: 2763-2771, 2017. [PubMed: 28777491] [Full Text: https://doi.org/10.1002/ajmg.a.38375]
Zaharieva, I. T., Sarkozy, A., Munot, P., Manzur, A., O'Grady, G., Rendu, J., Malfatti, E., Amthor, H., Servais, L., Urtizberea, J. A., Neto, O. A., Zanoteli, E., and 23 others. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum. Mutat. 39: 1980-1994, 2018. [PubMed: 30168660] [Full Text: https://doi.org/10.1002/humu.23635]