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STAC3 gene
URL of this page: https://medlineplus.gov/genetics/gene/stac3/

STAC3 gene

SH3 and cysteine rich domain 3

Normal Function

The STAC3 gene provides instructions for making a protein whose function is not completely understood. It plays a role in muscles used for movement (skeletal muscles). For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by changes in the concentration of certain charged atoms (ions) in muscle cells. The STAC3 protein aids in the process that triggers the release of calcium ions within muscle cells to start (initiate) muscle contraction.

The STAC3 protein interacts with two structures in muscle cells that are critical for calcium ion flow, dihydropyridine receptor (DHPR) and ryanodine receptor 1 (RYR1). However, STAC3's role in this formation is unknown. RYR1 forms a channel (the RYR1 channel) through which calcium ions can flow. In response to certain signals, DHPR turns on (activates) the RYR1 channel, and the activated RYR1 channel releases calcium ions stored in structures inside muscle cells. The resulting increase in the calcium ion concentration within muscle cells stimulates muscles to contract, allowing the body to move. The process by which certain chemical signals trigger muscle contraction is called excitation-contraction (E-C) coupling.

Health Conditions Related to Genetic Changes

STAC3 disorder

At least five mutations in the STAC3 gene have been found to cause STAC3 disorder (formerly known as Native American myopathy). This condition is a muscle disorder characterized by weakness, droopy eyelids (ptosis) and other distinctive facial features, joint deformities (contractures), and increased risk of a condition known as malignant hyperthermia, which is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures.

Mutations in the STAC3 gene reduce the amount or impair the function of the STAC3 protein. Although the mechanism is unclear, studies show that a shortage of working STAC3 protein affects the function of DHPR and prevents the release of calcium ions by RYR1 channels, resulting in a buildup of calcium in storage. A disruption in calcium ion release prevents muscles from contracting normally, leading to the muscle weakness characteristic of STAC3 disorder.

It is unclear how these STAC3 gene mutations lead to malignant hyperthermia in susceptible individuals. Mutations in other genes related to malignant hyperthermia activate the RYR1 channel improperly in response to certain drugs. As a result, large amounts of calcium ions are released from storage within muscle cells. An overabundance of available calcium ions causes skeletal muscles to contract abnormally, which leads to muscle rigidity. An increase in calcium ion concentration also activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). It is unknown if STAC3 gene mutations have a similar effect on RYR1 channel activity.

More About This Health Condition

Other Names for This Gene

  • SH3 AND CYSTEINE-RICH DOMAINS 3
  • STAC3 gene

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Campiglio M, Coste de Bagneaux P, Ortner NJ, Tuluc P, Van Petegem F, Flucher BE. STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation. Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):1376-1381. doi: 10.1073/pnas.1715997115. Epub 2018 Jan 23. Citation on PubMed or Free article on PubMed Central
  • Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, Saint-Amant L, Satish A, Cui WW, Zhou W, Sprague SM, Stamm DS, Powell CM, Speer MC, Franzini-Armstrong C, Hirata H, Kuwada JY. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun. 2013;4:1952. doi: 10.1038/ncomms2952. Citation on PubMed or Free article on PubMed Central
  • Linsley JW, Hsu IU, Groom L, Yarotskyy V, Lavorato M, Horstick EJ, Linsley D, Wang W, Franzini-Armstrong C, Dirksen RT, Kuwada JY. Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E228-E236. doi: 10.1073/pnas.1619238114. Epub 2016 Dec 21. Citation on PubMed or Free article on PubMed Central
  • Polster A, Nelson BR, Olson EN, Beam KG. Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):10986-91. doi: 10.1073/pnas.1612441113. Epub 2016 Sep 12. Citation on PubMed or Free article on PubMed Central
  • Polster A, Perni S, Bichraoui H, Beam KG. Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):602-6. doi: 10.1073/pnas.1423113112. Epub 2014 Dec 29. Citation on PubMed or Free article on PubMed Central
  • Wong King Yuen SM, Campiglio M, Tung CC, Flucher BE, Van Petegem F. Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9520-E9528. doi: 10.1073/pnas.1708852114. Epub 2017 Oct 23. Citation on PubMed or Free article on PubMed Central
  • Zaharieva IT, Sarkozy A, Munot P, Manzur A, O'Grady G, Rendu J, Malfatti E, Amthor H, Servais L, Urtizberea JA, Neto OA, Zanoteli E, Donkervoort S, Taylor J, Dixon J, Poke G, Foley AR, Holmes C, Williams G, Holder M, Yum S, Medne L, Quijano-Roy S, Romero NB, Faure J, Feng L, Bastaki L, Davis MR, Phadke R, Sewry CA, Bonnemann CG, Jungbluth H, Bachmann C, Treves S, Muntoni F. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum Mutat. 2018 Dec;39(12):1980-1994. doi: 10.1002/humu.23635. Epub 2018 Oct 11. Citation on PubMed

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