STIM1 – Tubular Aggregate Myopathy

Tubular aggregate myopathy (tubular aggregate myopathy) is an autosomal dominant skeletal muscle disorder characterized by the accumulation of membrane tubules in muscle fibres, leading to progressive proximal muscle weakness, elevated creatine kinase levels, scapular winging and external ophthalmoplegia. Heterozygous gain-of-function mutations in STIM1, the main endoplasmic reticulum Ca2+ sensor, disrupt intracellular calcium homeostasis and underlie this phenotype.

STIM1 mutations were first described in a German family with autosomal dominant tubular aggregate myopathy, where a novel missense variant in the first EF-hand domain, c.242G>A (p.Gly81Asp), was identified in two affected individuals exhibiting scapular winging, ventilatory failure, joint contractures and external ophthalmoplegia ([PMID:25953320]). Subsequent multi-family studies documented at least 49 patients from 42 unrelated families harboring heterozygous STIM1 mutations predominantly in the luminal EF-hand region, with clear segregation across generations ([PMID:25326555]).

Inheritance is autosomal dominant, with segregation of disease-causing variants in multiple large pedigrees. The variant spectrum includes mainly missense changes in the EF-hand domain (e.g., p.Asp84Gly, p.His109Asn), as well as rare frameshift and in-frame deletions in the CTID region. Recurrent mutations at hotspot residues (Asp84, His109, Arg304) account for a significant proportion of cases. The exemplar variant c.242G>A (p.Gly81Asp) is reported in two unrelated probands ([PMID:25953320]).

Functional assays across patient-derived myoblasts, heterologous expression systems and zebrafish models consistently demonstrate constitutive STIM1 clustering and enhanced or dysregulated store-operated Ca2+ entry (SOCE), leading to elevated resting cytosolic Ca2+ and muscle fibre pathology. For instance, TAM myoblasts with p.Gly81Asp show increased calcium influx on calcium imaging ([PMID:25953320]), while zebrafish expressing p.Arg304Trp recapitulate myopathic features ([PMID:24591628]). Animal and cellular models confirm that STIM1 gain-of-function underlies the TAM phenotype.

No credible conflicting evidence has been reported. All identified STIM1 variants associated with TAM exhibit concordant functional effects, and loss-of-function STIM1 mutations instead cause immunodeficiency, underscoring the tissue-specific consequences of STIM1 dysregulation.

Given the strong genetic and experimental evidence, STIM1 is a definitive TAM gene. Genetic testing for STIM1 variants in patients with tubular aggregate myopathy can provide molecular diagnosis, inform clinical management and enable genetic counselling. Early recognition of STIM1-mediated TAM is critical for prognosis and potential targeted interventions.

Key Take-home: Autosomal dominant STIM1 gain-of-function mutations cause tubular aggregate myopathy via dysregulated SOCE, and STIM1 genetic testing is essential for accurate diagnosis.

References

• Journal of medical genetics • 2014 • Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1 PMID:25326555
• American Journal of Human Genetics • 2013 • Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy PMID:23332920
• Neuromuscular Disorders • 2015 • 50 years to diagnosis: Autosomal dominant tubular aggregate myopathy caused by a novel STIM1 mutation. PMID:25953320
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis PMID:24591628
• Neuromuscular Disorders • 2017 • Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains. PMID:28624464

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