ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-functio...

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Published in:JCI insight 2024-03, Vol.9 (6)
Main Authors: Silva-Rojas, Roberto, Pérez-Guàrdia, Laura, Simon, Alix, Djeddi, Sarah, Treves, Susan, Ribes, Agnès, Silva-Hernández, Lorenzo, Tard, Céline, Laporte, Jocelyn, Böhm, Johann
Format: Article
Language:English
Subjects:
Animals
Blood Platelet Disorders
Calcium - metabolism
Dyslexia
Erythrocytes, Abnormal
Ichthyosis
Life Sciences
Mice
Migraine Disorders - drug therapy
Miosis - drug therapy
Miosis - genetics
Miosis - metabolism
Muscle Fatigue
Myopathies, Structural, Congenital - drug therapy
Myopathies, Structural, Congenital - genetics
Myopathies, Structural, Congenital - metabolism
ORAI1 Protein - genetics
ORAI1 Protein - metabolism
Spleen - abnormalities
Spleen - metabolism
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Summary:Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.174866