Tubular aggregate myopathy (TAM) is a progressive skeletal muscle disease associated with gain-of-function mutations in the ER Ca2+ sensor STIM1 that mediates store-operated Ca2+ entry (SOCE) across the Ca2+-release-activated (CRAC) Ca2+ channel ORAI1. A frameshift mutation in STIM1 inactivation domain, STIM1I484R, was identified in a TAM patient and reported to decrease SOCE.

Using ion imaging and electrophysiology, the authors of this article published in Cell Calcium and led by GCIR member Professor Nicolas Demaurex, show that the STIM1I484R mutation instead renders STIM1 constitutively active. In ion imaging experiments, STIM1I484R was less efficient than native STIM1 when expressed alone but enhanced SOCE and increased basal Ca2+ and Mn2+ influx when expressed together with ORAI1. In patch-clamp recordings, STIM1I484R generated larger pre-activated CRAC currents lacking slow Ca2+-dependent inhibition (SCDI). STIM1I484R was pre-recruited in plasma membrane clusters when co-expressed with ORAI1, as were mutants truncated at the frameshift residue or lacking EB-1-binding, which recapitulated STIM1I484R gain-of-function. When expressed alone in human primary myoblasts, STIM1I484R was pre-recruited in large clusters and increased basal Ca2+ entry.

These observations establish that STIM1I484R confers a gain of CRAC channel function due to the loss of critical inhibitory C-terminal domains that prevent STIM1 binding to ORAI1, enable STIM1 trapping by microtubules, and mediate SCDI, providing a mechanistic explanation for the muscular defects of TAM patients bearing this mutation.

Full article: https://doi.org/10.1016/j.ceca.2022.102615

Why is this article important?

Tubular aggregate myopathy (TAM) is a disorder that mainly affects skeletal muscles, which are the muscles the body uses for movement. The muscles of the legs are most affected, but the muscles of the arms may also be involved. Symptoms include muscle pain, cramps, weakness or stiffness, and exercise-induced muscle fatigue. Affected individuals may have an unusual walking style or difficulty running, climbing stairs, or rising from a squatting position.

This disease may be caused by genetic changes in the STIM1 or ORAI1 genes. STIM1 is a single-pass transmembrane protein that senses endoplasmic reticulum calcium depletion and the ORAI1 channel protein triggers extracellular Ca2+ entry. The research group of Professor Nicolas Demaurex, characterised here the dysregulation of Ca2+ homeostasis associated with the expression of a mutant version of STIM1. By expressing the mutant protein in cells lacking STIM, they show that this mutation causes TAM not by reduction (as previously reported) but by excessive Ca2+ entry, implying that patients carrying this mutation could benefit from drugs that inhibit ORAI1 channels.

This study was supported by the National Research Foundation of Korea, the Medical Research Center Program and by the Swiss National Foundation.