Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

Hum Mutat. 2020 Jan;41(1):17-37. doi: 10.1002/humu.23899. Epub 2019 Sep 15.


Calcium (Ca2+ ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca2+ entry, storage, and release. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling extracellular Ca2+ entry, and mainly relies on the accurate interplay between the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca2+ homeostasis and are associated with severe human disorders. Recessive loss-of-function mutations impair SOCE and cause combined immunodeficiency, while dominant gain-of-function mutations induce excessive extracellular Ca2+ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.

Keywords: ORAI1; STIM1; Stormorken syndrome; store-operated calcium entry; tubular aggregate myopathy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alleles
  • Biomarkers*
  • Blood Platelet Disorders / diagnosis*
  • Blood Platelet Disorders / genetics*
  • Calcium / metabolism
  • Disease Management
  • Dyslexia / diagnosis*
  • Dyslexia / genetics*
  • Erythrocytes, Abnormal
  • Gain of Function Mutation
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Ichthyosis / diagnosis*
  • Ichthyosis / genetics*
  • Migraine Disorders / diagnosis*
  • Migraine Disorders / genetics*
  • Miosis / diagnosis*
  • Miosis / genetics*
  • Muscle Fatigue / genetics
  • Mutation*
  • Myopathies, Structural, Congenital / diagnosis*
  • Myopathies, Structural, Congenital / genetics*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • ORAI1 Protein / genetics
  • ORAI1 Protein / metabolism
  • Phenotype
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Spleen / abnormalities*
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism


  • Biomarkers
  • Neoplasm Proteins
  • ORAI1 Protein
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Calcium

Supplementary concepts

  • Stormorken Syndrome