[en] SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca(2+) release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.
Disciplines :
Neurology Pediatrics
Author, co-author :
Zaharieva, Irina T.
Sarkozy, Anna
Munot, Pinki
Manzur, Adnan
O'Grady, Gina
Rendu, John
Malfatti, Eduardo
Amthor, Helge
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques > Neuropédiatrie
Bachmann, C., Jungbluth, H., Muntoni, F., Manzur, A. Y., Zorzato, F., & Treves, S. (2017). Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations. Human Molecular Genetics, 26(2), 320–332. https://doi.org/10.1093/hmg/ddw388
Bower, N. I., de la Serrana, D. G., Cole, N. J., Hollway, G. E., Lee, H. T., Assinder, S., & Johnston, I. A. (2012). Stac3 is required for myotube formation and myogenic differentiation in vertebrate skeletal muscle. Journal of Biological Chemistry, 287(52), 43936–43949. https://doi.org/10.1074/jbc.M112.361311
Campiglio, M., & Flucher, B. E. (2017). STAC3 stably interacts through its C1 domain with CaV1.1 in skeletal muscle triads. Scientific Reports, 7, 41003. https://doi.org/10.1038/srep41003
Censier, K., Urwyler, A., Zorzato, F., & Treves, S. (1998). Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors. Journal of Clinical Investigation, 101(6), 1233–1242. https://doi.org/10.1172/jci993
Cong, X., Doering, J., Grange, R. W., & Jiang, H. (2016). Defective excitation-contraction coupling is partially responsible for impaired contractility in hindlimb muscles of Stac3 knockout mice. Scientific Reports, 6, 26194. https://doi.org/10.1038/srep26194
Cong, X., Doering, J., Mazala, D. A., Chin, E. R., Grange, R. W., & Jiang, H. (2016). The SH3 and cysteine-rich domain 3 (Stac3) gene is important to growth, fiber composition, and calcium release from the sarcoplasmic reticulum in postnatal skeletal muscle. Skeletal Muscle, 6, 17. https://doi.org/10.1186/s13395-016-0088-4
Dubowitz, V., Sewry, C. A., & Oldfors, A. (2013). Muscle biopsy: A practical approach (4th ed.). Philadelphia, PA: Saunders Elsevier
Flucher, B. E., Phillips, J. L., & Powell, J. A. (1991). Dihydropyridine receptor alpha subunits in normal and dysgenic muscle in vitro: Expression of alpha 1 is required for proper targeting and distribution of alpha 2. Journal of Cell Biology, 115(5), 1345–1356
Grabner, M., Dirksen, R. T., Suda, N., & Beam, K. G. (1999). The II-III loop of the skeletal muscle dihydropyridine receptor is responsible for the Bi-directional coupling with the ryanodine receptor. Journal of Biological Chemistry, 274(31), 21913–21919
Grzybowski, M., Schanzer, A., Pepler, A., Heller, C., Neubauer, B. A., & Hahn, A. (2017). Novel STAC3 mutations in the first non-Amerindian patient with Native American myopathy. Neuropediatrics, 48, 451–455. 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., … Kuwada, J. Y. (2013). Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nature Communications, 4, 1952. https://doi.org/10.1038/ncomms2952
Lim, W. A., & Richards, F. M. (1994). Critical residues in an SH3 domain from Sem-5 suggest a mechanism for proline-rich peptide recognition. Nature Structural Biology, 1(4), 221–225
Linsley, J. W., Hsu, I. U., Groom, L., Yarotskyy, V., Lavorato, M., Horstick, E. J., … Kuwada, J. Y. (2017). Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. Proceedings of the National Academy of Sciences of the United States of America, 114(2), E228–E236. https://doi.org/10.1073/pnas.1619238114
Linsley, J. W., Hsu, I. U., Wang, W., & Kuwada, J. Y. (2017). Transport of the alpha subunit of the voltage gated L-type calcium channel through the sarcoplasmic reticulum occurs prior to localization to triads and requires the beta subunit but not Stac3 in skeletal muscles. Traffic, 18(9), 622–632. https://doi.org/10.1111/tra.12502
Mayer, B. J., & Baltimore, D. (1993). Signalling through SH2 and SH3 domains. Trends in Cell Biology, 3(1), 8–13
Morton, C. J., & Campbell, I. D. (1994). SH3 domains. Molecular ‘Velcro’. Current Biology, 4(7), 615–617
Nakai, J., Tanabe, T., Konno, T., Adams, B., & Beam, K. G. (1998). Localization in the II-III loop of the dihydropyridine receptor of a sequence critical for excitation-contraction coupling. Journal of Biological Chemistry, 273(39), 24983–24986
Nelson, B. R., Wu, F., Liu, Y., Anderson, D. M., McAnally, J., Lin, W., … Olson, E. N. (2013). Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 11881–11886. https://doi.org/10.1073/pnas.1310571110
Nishi, M. (1995). [Excitation-contraction uncoupling and muscular degeneration lacking functional skeletal muscle ryanodine-receptor gene]. Tanpakushitsu Kakusan Koso, 40(14), 2181–2187
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera: A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612. https://doi.org/10.1002/jcc.20084
Polster, A., Nelson, B. R., Olson, E. N., & Beam, K. G. (2016). Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proceedings of the National Academy of Sciences of the United States of America, 113(39), 10986–10991. https://doi.org/10.1073/pnas.1612441113
Polster, A., Nelson, B. R., Papadopoulos, S., Olson, E. N., & Beam, K. G. (2018). Stac proteins associate with the critical domain for excitation-contraction coupling in the II-III loop of CaV1.1. Journal of General Physiology, 150, 613–624. https://doi.org/10.1085/jgp.201711917
Polster, A., Perni, S., Bichraoui, H., & Beam, K. G. (2015). Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 602–606. https://doi.org/10.1073/pnas.1423113112
Reinholt, B. M., Ge, X., Cong, X., Gerrard, D. E., & Jiang, H. (2013). Stac3 is a novel regulator of skeletal muscle development in mice. PLoS One, 8(4), e62760. https://doi.org/10.1371/journal.pone.0062760
Rios, E., & Pizarro, G. (1991). Voltage sensor of excitation-contraction coupling in skeletal muscle. Physiological Reviews, 71(3), 849–908. https://doi.org/10.1152/physrev.1991.71.3.849
Sali, A., & Blundell, T. L. (1993). Comparative protein modelling by satisfaction of spatial restraints. Journal of Molecular Biology, 234(3), 779–815. https://doi.org/10.1006/jmbi.1993.1626
Schartner, V., Romero, N. B., Donkervoort, S., Treves, S., Munot, P., Pierson, T. M., … Laporte, J. (2017). Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathologica, 133(4), 517–533. https://doi.org/10.1007/s00401-016-1656-8
Stamm, D. S., Aylsworth, A. S., Stajich, J. M., Kahler, S. G., Thorne, L. B., Speer, M. C., & Powell, C. M. (2008). Native American myopathy: Congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. American Journal of Medical Genetics A, 146A(14), 1832–1841. https://doi.org/10.1002/ajmg.a.32370
Telegrafi, A., Webb, B. D., Robbins, S. M., Speck-Martins, C. E., FitzPatrick, D., Fleming, L., … Sobreira, N. L. M. (2017). Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. American Journal of Medical Genetics A, 173, 2763–2771. https://doi.org/10.1002/ajmg.a.38375
Ward, C. W., Schneider, M. F., Castillo, D., Protasi, F., Wang, Y., Chen, S. R., & Allen, P. D. (2000). Expression of ryanodine receptor RyR3 produces Ca2+ sparks in dyspedic myotubes. Journal of Physiology, 525(Pt 1), 91–103
Wong King Yuen, S. M., Campiglio, M., Tung, C. C., Flucher, B. E., & Van Petegem, F. (2017). Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proceedings of the National Academy of Sciences of the United States of America, 114(45), E9520–E9528. https://doi.org/10.1073/pnas.1708852114
Zafra-Ruano, A., & Luque, I. (2012). Interfacial water molecules in SH3 interactions: Getting the full picture on polyproline recognition by protein-protein interaction domains. FEBS Letters, 586(17), 2619–2630. https://doi.org/10.1016/j.febslet.2012.04.057
Zhang, C., Roque, D., Ehrisman, J. A., DiSanto, N., Broadwater, G., Doll, K. M., … Havrilesky, L. J. (2015). Lumbee Native American ancestry and the incidence of aggressive histologic subtypes of endometrial cancer. Gynecologic Oncology Reports, 13, 49–52. https://doi.org/10.1016/j.gore.2015.06.004
Zorzato, F., Scutari, E., Tegazzin, V., Clementi, E., & Treves, S. (1993). Chlorocresol: An activator of ryanodine receptor-mediated Ca2+ release. Molecular Pharmacology, 44(6), 1192–1201