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

Gilles Morin, Valérie Biancalana, Andoni Echaniz-Laguna, Jean Baptiste Noury, Xavière Lornage, Maurizio Moggio, Michela Ripolone, Raffaella Violano, Pascale Marcorelles, Denis Maréchal, Florence Renaud, Claude Alain Maurage, Céline Tard, Jean Marie Cuisset, Jocelyn Laporte, Johann Böhm

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)17-37
JournalHuman Mutation
Volume41
Issue number1
DOIs
Publication statusPublished - 2020

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Keywords

  • ORAI1
  • STIM1
  • store-operated calcium entry
  • Stormorken syndrome
  • tubular aggregate myopathy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Morin, G., Biancalana, V., Echaniz-Laguna, A., Noury, J. B., Lornage, X., Moggio, M., Ripolone, M., Violano, R., Marcorelles, P., Maréchal, D., Renaud, F., Maurage, C. A., Tard, C., Cuisset, J. M., Laporte, J., & Böhm, J. (2020). Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation. Human Mutation, 41(1), 17-37. https://doi.org/10.1002/humu.23899