STAC3variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

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 Ca release. Co-immunoprecipitation of STAC3 with Ca 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and Ca 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 1.1 sarcolemma mislocalization or impaired STAC3-Ca 1.1 interaction.

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

“…In addition, 18 patients of African, Middle Eastern, and South American ancestry presenting symptoms ranging from severe prenatal/neonatal onset to slowly progressive congenital myopathy (6 months–22 years old) were found homozygous or compound heterozygous for the p.W84S mutation. Thus, the p.W284S mutation is not restricted to the Native American population [ 68 ]. The first NAM-affected patient of Turkish origin carries two heterozygous variants (c.862A>T; p.K288* and c.432+4A>T), close to but not into the p.W284S region of the STAC3 gene [ 69 ].…”

Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation–contraction coupling

“…STAC3 is the target for mutations causing the rare neuromuscular disease Native American myopathy (NAM) ( 42 , 60 ). NAM is an autosomal recessive disease ( 94 , 95 , 96 , 97 ). Cases were first identified in members of the Lumbee Tribe of North Carolina; the prevalence within this community is difficult to estimate because of their cultural isolation ( 98 ).…”

Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine

“…Other cases have been since reported [223][224][225][226]. In addition, Cav1.1 dysfunction is the likely mechanism responsible for the disease in Native American myopathy and other congenital myopathies caused primarily by mutations in STAC3 [227][228][229]. Indeed, Stac3 protein (SH3 and cysteinerich domain 3) is an essential component of the EC coupling apparatus and enhances Cav1.1 channel expression [230][231][232].…”