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Calsequestrin-1 (CASQ1) is the principal Ca²⁺‐binding protein of skeletal muscle sarcoplasmic reticulum. Tubular aggregate myopathy (TAM, MONDO:0008051) is a rare, dominantly inherited myopathy characterized by exercise intolerance, myalgia, and accumulation of SR‐derived tubular aggregates in muscle fibers. Recent studies have identified heterozygous CASQ1 missense variants in patients with TAM, expanding the genetic etiology beyond STIM1 and ORAI1 gain-of-function mutations (PMID:28895244, PMID:39126637).
Genetic evidence supports an autosomal dominant mode of inheritance for CASQ1-related TAM. Initial reports described three novel missense mutations in four unrelated probands: p.Asp44Asn, p.Gly103Asp, and p.Ile385Thr (PMID:28895244). A subsequent cohort of 22 patients from 12 families, including a founder p.Asp244Gly and one p.Gly103Asp carrier, further confirmed segregation of CASQ1 variants with TAM (PMID:30258016). Overall, at least 24 probands across 12 families with segregating heterozygous missense variants have been reported.
The CASQ1 variant spectrum in TAM comprises exclusively missense changes affecting conserved residues in high-affinity Ca²⁺ binding or polymerization domains. Notably recurrent p.Asp244Gly and p.Gly103Asp alleles have been observed in multiple pedigrees, consistent with a founder effect and mutational hotspot. A representative variant is c.308G>A (p.Gly103Asp), which disrupts Ca²⁺-dependent polymerization.
Functional studies demonstrate that CASQ1 TAM mutants impair Ca²⁺ handling in muscle. In vitro assays (turbidity, dynamic light scattering) show reduced Ca²⁺-dependent aggregation for p.Asp44Asn and p.Gly103Asp, altered protease susceptibility, and, in single fibers, diminished caffeine‐induced Ca²⁺ release (PMID:28895244). Expression of mutants in Casq1 knockout mouse fibers confirms loss of Ca²⁺ storage capacity and failure to inhibit store-operated Ca²⁺ entry, mirroring TAM pathophysiology (PMID:39126637).
No studies to date have refuted the CASQ1–TAM association, and experimental data are concordant with clinical phenotypes. The weight of genetic segregation across multiple families combined with robust functional assays fulfills ClinGen criteria for a Strong gene–disease association.
Key Take-home: Heterozygous CASQ1 missense variants cause autosomal dominant tubular aggregate myopathy by disrupting Ca²⁺ polymerization and SR Ca²⁺ homeostasis, supporting diagnostic testing and targeted management in affected families.
Gene–Disease AssociationStrong24 probands across 12 families; heterozygous missense segregation and concordant functional data ([PMID:28895244], [PMID:30258016]) Genetic EvidenceStrong24 patients from 12 families with autosomal dominant CASQ1 missense variants reaching ClinGen genetic cap Functional EvidenceModerateMultiple in vitro, muscle fiber, and mouse model assays demonstrate impaired Ca²⁺ polymerization, storage, and SOCE inhibition in TAM variants |