Journal article
STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility
Human mutation, Vol.39(12), pp.1980-1994
12/01/2018
DOI: 10.1002/humu.23635
PMID: 30168660
Abstract
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 Ca(V)1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and Ca(V)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 Ca(V)1.1 sarcolemma mislocalization or impaired STAC3-Ca(V)1.1 interaction.
Details
- Title: Subtitle
- STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility
- Creators
- Irina T. Zaharieva - Great Ormond Street HospitalAnna Sarkozy - Great Ormond Street HospitalPinki Munot - Great Ormond Street HospitalAdnan Manzur - Great Ormond Street HospitalGina O'Grady - University of SydneyJohn Rendu - Centre Hospitalier Universitaire de GrenobleEduardo Malfatti - Institut de MyologieHelge Amthor - Université de Versailles Saint-Quentin-en-YvelinesLaurent Servais - Hôpital Armand-TrousseauJ. Andoni Urtizberea - Hôpital Marin de HendayeOsorio Abath Neto - Univ Sao Paulo, Fac Med, Dept Neurol, Sao Paulo, BrazilEdmar Zanoteli - Universidade de São PauloSandra Donkervoort - National Institutes of HealthJuliet Taylor - Genetic Health Service New Zealand, Auckland, New Zealand.Joanne Dixon - Genetic Health Service New Zealand, Christchurch, New Zealand.Gemma Poke - Wellington Management CompanyA. Reghan Foley - National Institutes of HealthChris Holmes - Great Ormond Street HospitalGlyn Williams - Great Ormond Street HospitalMuriel Holder - Guy's HospitalSabrina Yum - Children's Hospital of PhiladelphiaLivija Medne - Children's Hospital of PhiladelphiaSusana Quijano-Roy - Hôpital Raymond-PoincaréNorma B. Romero - Institut de MyologieJulien Faure - Centre Hospitalier Universitaire de GrenobleLucy Feng - Great Ormond Street HospitalLaila Bastaki - Kuwait Medical Genetics Centre, Maternity Hospital, Kuwait City, Kuwait.Mark R. Davis - Pathwest Laboratory MedicineRahul Phadke - Great Ormond Street HospitalCaroline A. Sewry - Great Ormond Street HospitalCarsten G. Bonnemann - National Institutes of HealthHeinz Jungbluth - University Hospital of BaselChristoph Bachmann - University Hospital of BaselSusan Treves - University Hospital of BaselFrancesco Muntoni - Great Ormond Street Hospital
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.39(12), pp.1980-1994
- Publisher
- Wiley
- DOI
- 10.1002/humu.23635
- PMID
- 30168660
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Number of pages
- 15
- Grant note
- NeRAB Association 2012-305121 / FP7 Health National Institute for Neurological Disorders and Stroke/NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) 31003A-169316 / Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung; Austrian Science Fund (FWF) MDA577346 / Muscular Dystrophy Association ZIANS003129 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) OPOStiftung NIHR Great Ormond Street Hospital Biomedical Research Centre 779257 / Horizon 2020 Framework Programme
- Language
- English
- Date published
- 12/01/2018
- Academic Unit
- Pathology
- Record Identifier
- 9984277458602771
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