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STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

Research output: Contribution to journalArticle

Irina T Zaharieva, Anna Sarkozy, Pinki Munot, Adnan Manzur, Gina O'Grady, John Rendu, Eduardo Malfatti, Helge Amthor, Laurent Servais, J Andoni Urtizberea, Osorio Abath Neto, Edmar Zanoteli, Sandra Donkervoort, Juliet Taylor, Joanne Dixon, Gemma Poke, A Reghan Foley, Chris Holmes, Glyn Williams, Muriel Holder & 15 more Sabrina Yum, Livija Medne, Susana Quijano-Roy, Norma B Romero, Julien Fauré, Lucy Feng, Laila Bastaki, Mark R Davis, Rahul Phadke, Caroline A Sewry, Carsten G Bönnemann, Heinz Jungbluth, Christoph Bachmann, Susan Treves, Francesco Muntoni

Original languageEnglish
Pages (from-to)1980-1994
Number of pages15
JournalHuman Mutation
Issue number12
Early online date31 Aug 2018
Publication statusPublished - Dec 2018

King's Authors


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 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.

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