STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.
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 i...
| Κύριοι συγγραφείς: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Μορφή: | Journal article |
| Γλώσσα: | English |
| Έκδοση: |
Wiley
2018
|
| _version_ | 1826272920169611264 |
|---|---|
| author | Zaharieva, IT Sarkozy, A Munot, P Manzur, A O'Grady, G Rendu, J Malfatti, E Amthor, H Prof Laurent Servais 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 Fauré, J Feng, L Bastaki, L Davis, MR Phadke, R Sewry, CA Bönnemann, CG Jungbluth, H Bachmann, C Treves, S Muntoni, F |
| author_facet | Zaharieva, IT Sarkozy, A Munot, P Manzur, A O'Grady, G Rendu, J Malfatti, E Amthor, H Prof Laurent Servais 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 Fauré, J Feng, L Bastaki, L Davis, MR Phadke, R Sewry, CA Bönnemann, CG Jungbluth, H Bachmann, C Treves, S Muntoni, F |
| author_sort | Zaharieva, IT |
| collection | OXFORD |
| description | 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 Ca2+ release. Co‐immunoprecipitation of STAC3 with CaV1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV1.1 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 CaV1.1 sarcolemma mislocalization or impaired STAC3‐CaV1.1 interaction. |
| first_indexed | 2024-03-06T22:20:11Z |
| format | Journal article |
| id | oxford-uuid:54c4177b-aa57-478f-b0d9-a31e1d877de4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:20:11Z |
| publishDate | 2018 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:54c4177b-aa57-478f-b0d9-a31e1d877de42022-03-26T16:39:59ZSTAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:54c4177b-aa57-478f-b0d9-a31e1d877de4EnglishSymplectic ElementsWiley2018Zaharieva, ITSarkozy, AMunot, PManzur, AO'Grady, GRendu, JMalfatti, EAmthor, HProf Laurent ServaisUrtizberea, JANeto, OAZanoteli, EDonkervoort, STaylor, JDixon, JPoke, GFoley, ARHolmes, CWilliams, GHolder, MYum, SMedne, LQuijano-Roy, SRomero, NBFauré, JFeng, LBastaki, LDavis, MRPhadke, RSewry, CABönnemann, CGJungbluth, HBachmann, CTreves, SMuntoni, FSH3 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 Ca2+ release. Co‐immunoprecipitation of STAC3 with CaV1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV1.1 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 CaV1.1 sarcolemma mislocalization or impaired STAC3‐CaV1.1 interaction. |
| spellingShingle | Zaharieva, IT Sarkozy, A Munot, P Manzur, A O'Grady, G Rendu, J Malfatti, E Amthor, H Prof Laurent Servais 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 Fauré, J Feng, L Bastaki, L Davis, MR Phadke, R Sewry, CA Bönnemann, CG Jungbluth, H Bachmann, C Treves, S Muntoni, F STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. |
| title | STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. |
| title_full | STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. |
| title_fullStr | STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. |
| title_full_unstemmed | STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. |
| title_short | STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. |
| title_sort | stac3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility |
| work_keys_str_mv | AT zaharievait stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT sarkozya stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT munotp stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT manzura stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT ogradyg stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT renduj stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT malfattie stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT amthorh stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT proflaurentservais stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT urtizbereaja stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT netooa stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT zanotelie stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT donkervoorts stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT taylorj stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT dixonj stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT pokeg stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT foleyar stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT holmesc stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT williamsg stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT holderm stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT yums stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT mednel stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT quijanoroys stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT romeronb stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT faurej stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT fengl stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT bastakil stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT davismr stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT phadker stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT sewryca stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT bonnemanncg stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT jungbluthh stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT bachmannc stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT trevess stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility AT muntonif stac3variantscauseacongenitalmyopathywithdistinctivedysmorphicfeaturesandmalignanthyperthermiasusceptibility |