STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

Abstract

Store-operated Ca 2+ entry (SOCE) is a ubiquitous and essential mechanism regulating Ca 2+ homeostasis in all tissues, and controls a wide range of cellular functions including keratinocyte differentiation, osteoblastogenesis and osteoclastogenesis, T cell proliferation, platelet activation, and muscle contraction. The main SOCE actors are STIM1 and ORAI1. Depletion of the reticular Ca 2+ stores induces oligomerization of the luminal Ca 2+ sensor STIM1, and the oligomers activate the plasma membrane Ca 2+ channel ORAI1 to trigger extracellular Ca 2+ entry. Mutations in STIM1 and ORAI1 result in abnormal SOCE and lead to multi-systemic disorders. Recessive loss-of-function mutations are associated with CRAC (Ca 2+ release-activated Ca 2+ ) channelopathy, involving immunodeficiency and autoimmunity, muscular hypotonia, ectodermal dysplasia, and mydriasis. In contrast, dominant STIM1 and ORAI1 gain-of-function mutations give rise to tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), forming a clinical spectrum encompassing muscle weakness, thrombocytopenia, ichthyosis, hyposplenism, short stature, and miosis. Functional studies on patient-derived cells revealed that CRAC channelopathy mutations impair SOCE and extracellular Ca 2+ influx, while TAM/STRMK mutations induce excessive Ca 2+ entry through SOCE over-activation. In accordance with the opposite pathomechanisms underlying both disorders, CRAC channelopathy and TAM/STRMK patients show mirror phenotypes at the clinical and molecular levels, and the respective animal models recapitulate the skin, bones, immune system, platelet, and muscle anomalies. Here we review and compare the clinical presentations of CRAC channelopathy and TAM/STRMK patients and the histological and molecular findings obtained on human samples and murine models to highlight the mirror phenotypes in different tissues, and to point out potentially undiagnosed anomalies in patients, which may be relevant for disease management and prospective therapeutic approaches.

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

“…We believe that preclinical investigations could benefit also from a preliminary phenotypic in vitro screening based upon the findings here reported, i.e., upon the ability of candidate SOCE/CRAC inhibitors to counteract the differentiation alterations associated with Ca 2+ overload. As it is usually desired for neuromusculuar disorders (Silva-Rojas et al, 2020;van Putten et al, 2020), a such experimental approach could finally allow a reliable translation in the clinical management of TAM patients.…”

Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle

“…This suggests that the expression of STIM1-R304Q does not significantly affect the terminal differentiation of skeletal muscle and again confirms that STIM1 is not a critical protein for the terminal differentiation of skeletal muscle [7,8,17]. Human patients carrying STIM1-R304W (another mutant at R304) show skeletal muscle atrophy [11]. Based on no significant change in myotube width by STIM1-R304Q, it seems that the atrophy induced by STIM1-R304W may not be due to the decrease in the width of each muscle fiber but to a reduction in the total number of muscle fibers.…”

“…For example, congenital myopathies have been associated with E136X; muscular hypotonia with R429C; tubular aggregate myopathy with N80T, G81D, L96V, F108I, H109R, I115F, or I484R; skeletal muscle atrophy and progressive muscle weaknesses with H72Q, D84G, H109N, H109R, or R304W. STIM1 R304 is located in a coiled-coil domain of STIM1, and human patients with substitution of the arginine at residue 304 by tryptophan (STIM1-R304W, a constitutively active form of STIM1) show Stormorken syndrome, which is a multisystemic disease characterized by skeletal muscle phenotypes, including tubular aggregate myopathy, muscle spasms, muscle weakness, atrophy, lack of endurance, and hematological phenotypes [5,[9][10][11]. Studies on STIM1-R304W with cells from patients with Stormorken syndrome or model mice carrying STIM1-R304W suggest that excessive SOCE is a cause of multisystemic defects caused by STIM1-R304W [4,5,12,13].…”

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

“…TAM phenotype is clinical heterogeneous ranging from slowly progressive proximal muscle weakness predominantly affecting the lower limbs, with adult onset (>35 year), to myalgia only. Serum creatine kinase is usually elevated, and patients may develop eye movement disabilities and joint contractures during disease progression [ 74 , 94 , 98 ]. Notably, the same STIM1 mutations can also be responsible both for the STRMK [ 89 , 90 , 99 ] and the York syndrome [ 86 ], emphasizing how all these conditions represent a continuum.…”