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Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation
Author(s) -
Morin Gilles,
Biancalana Valérie,
EchanizLaguna Andoni,
Noury JeanBaptiste,
Lornage Xavière,
Moggio Maurizio,
Ripolone Michela,
Violano Raffaella,
Marcorelles Pascale,
Maréchal Denis,
Renaud Florence,
Maurage ClaudeAlain,
Tard Céline,
Cuisset JeanMarie,
Laporte Jocelyn,
Böhm Johann
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23899
Subject(s) - biology , orai1 , myopathy , mutation , stim1 , phenotype , haploinsufficiency , microbiology and biotechnology , loss function , genetics , extracellular , muscle weakness , endocrinology , endoplasmic reticulum , anatomy , gene
Calcium (Ca 2+ ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca 2+ entry, storage, and release. Store‐operated Ca 2+ entry (SOCE) is a major mechanism controlling extracellular Ca 2+ entry, and mainly relies on the accurate interplay between the Ca 2+ sensor STIM1 and the Ca 2+ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca 2+ 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 Ca 2+ 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.