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Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains
- Publication Year :
- 2017
-
Abstract
- Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.
- Subjects :
- 0301 basic medicine
Male
Models, Molecular
Exome sequencing
DNA Mutational Analysis
Cell Culture Techniques
medicine.disease_cause
Pediatrics
Dyslexia
0302 clinical medicine
Hypocalcaemia
Genetics (clinical)
Blood Platelet Disorders
Mutation
Ichthyosis
Middle Aged
Miosis
Perinatology and Child Health
Store-operated calcium entry
Magnetic Resonance Imaging
Neoplasm Proteins
Neurology
STIM1
Stormorken syndrome
Tubular aggregate myopathy
York platelet syndrome
Pediatrics, Perinatology and Child Health
Neurology (clinical)
Muscle Fatigue
Female
medicine.symptom
Myopathies, Structural, Congenital
inorganic chemicals
Adult
Asplenia
Migraine Disorders
Erythrocytes, Abnormal
Socio-culturale
03 medical and health sciences
medicine
Humans
Stromal Interaction Molecule 1
Myopathy
Muscle, Skeletal
Genetic Association Studies
Family Health
business.industry
Fibroblasts
medicine.disease
NAD
Bleeding diathesis
Microscopy, Electron
030104 developmental biology
Immunology
Calcium
business
030217 neurology & neurosurgery
Spleen
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....08f602728c67ab79a24d787c8492fde8