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

Human Mutation
Irina ZaharievaFrancesco Muntoni

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 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 pa...Continue Reading

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Mar 31, 2020·Pflügers Archiv : European journal of physiology·Bernhard E Flucher
Apr 30, 2019·Human Genetics·Katrina L MealeyMichael H Court
Jan 14, 2021·Journal of Biomedical Science·Po-Jui HsuChiou-Hwa Yuh
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Jul 15, 2021·Nature Reviews. Molecular Cell Biology·James J DowlingMelissa J Spencer

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