Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1

Abstract

Background Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or doublewalled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene. Methods The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum. Results We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EFhand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adultonset myalgia without muscle weakness and normal CK levels. Conclusions The present study expands the phenotypical spectrum of STIM1-related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign.

50 years to diagnosis: Autosomal dominant tubular aggregate myopathy caused by a novel STIM1 mutation

“…Other genetic myopathies with the morphological hallmark of tubular aggregates are the periodic paralyses of hypo-, hyper-, and normokalemic types, congenital myotonias or channelopathies, congenital myasthenic syndrome due to mutations in the GFPT1 gene and the glycogen storage disease type X [5]. Recently, mutations in the gene encoding stromal interaction molecule 1 (STIM1) have been identified in autosomal dominant tubular aggregate myopathy [MIM 160565] [7][8][9] and in a rare autosomal dominant syndrome featuring bleeding tendency, hematological abnormalities, asplenia, ichthyosis, congenital miosis, and tubular aggregate myopathy (Stormorken syndrome [MIM 185070]) [10,11]. STIM1 is the main calcium sensor of the sarcoplasmic reticulum and is crucial to maintain intracellular calcium homeostasis of muscle fibers [12,13].…”

Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1

“…The aggregation-like appearance is distinct from that in C2C12 myoblasts transfected with STIM1 harboring EF hand mutations, which exhibit numerous punctalike small clusters in cytoplasm. 4,6 Furthermore, intracellular Ca 21 measurements revealed that the Ca 21 influx is significantly decreased in the cells transfected with the CTID mutant compared to the wild-type STIM1-transfected cells. This result is in marked contrast to the previous reports, in which increased Ca 21 influx caused by constitutive activation of SOCE was observed.…”

“…10 All STIM1 mutations in TAM reported so far are missense mutations residing in the EF hand (EF1 and EF2 in figure 2B), and this region is considered a hotspot. [4][5][6] These mutations are presumed to induce the constitutive activation of ORAI1 and cause excessive Ca 21 influx into muscle cells.…”

“…3 Recently, several mutations in stromal interaction molecule 1 (STIM1), a Ca 21 sensor in SR, have been identified in dominantly inherited TAM (OMIM #160565). [4][5][6] All mutations demonstrated so far have been missense mutations located in the EF hand of the N-terminal luminal region and are thought to disrupt the Ca 21 binding to this region. In this article, we present a dominant TAM family in whom a novel insertion mutation was identified in the C-terminal inhibitory domain (CTID) located in the cytoplasmic region of STIM1 and investigate the functional significance of the mutation using cultured cells.…”

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

“…Muscle weakness is generally only mild in the adultonset cases and some of the patients with an ORAI1 mutation presented only with exertional cramps [97]. Similarly, the phenotype of patients with STIM1 mutations includes cases with (post-exercise) myalgia, fatigability, and calf hypertrophy without muscle weakness [98]. Interestingly, most STIM1 mutations identified in patients are located within the NH 2 terminal EF hand Ca 2+ binding domain of Stim1, leading to a constitutively active molecule that oligomerizes and clusters at ER/PM junctions independently of Ca 2+ store depletion.…”