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

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.

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

“…Pupillary dysfunction is a main clinical sign of CRAC channelopathy and TAM/STRMK. While CRAC channelopathy patients typically show iris dilatation (mydriasis) ( Feske et al, 2006 ; Picard et al, 2009 ; Fuchs et al, 2012 ; Lian et al, 2018 ), the inverse phenotype of light-insensitive iris hypercontraction (miosis) is a hallmark of TAM/STRMK, and results in migraine and reduced night vision ( Misceo et al, 2014 ; Morin et al, 2014 , 2020 ; Nesin et al, 2014 ; Markello et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Harris et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Claeys et al, 2020 ; Sura et al, 2020 ). Mydriasis and miosis have, however, not been described in murine models for CRAC channelopathy or TAM/STRMK.…”

“…Eye movement relies on the rapid and concerted contraction of six striated extraocular muscles, and ophthalmoplegia including upward gaze paresis ( Bohm et al, 2013 ; Noury et al, 2017 ), lateral gaze paresis ( Morin et al, 2020 ), or reduced lateral and/or upward gaze ( Bohm et al, 2014 ; Hedberg et al, 2014 ; Markello et al, 2015 ; Walter et al, 2015 ; Harris et al, 2017 ; Noury et al, 2017 ) is commonly seen in TAM/STRMK patients. In accordance, the TAM/STRMK mouse model harboring the most common STIM1 GoF mutation R304W also features an upward gaze paresis ( Silva-Rojas et al, 2019 ).…”

“…In the absence of SOCE, CRAC channelopathy patients present with thermoregulatory instability and anhidrosis accompanied by heat intolerance, dry skin, and eczema ( Feske et al, 2006 ; Fuchs et al, 2012 ; Schaballie et al, 2015 ; Lian et al, 2018 ). Skin anomalies including eczema and ichthyosis are also commonly seen in TAM/STRMK patients ( Misceo et al, 2014 ; Morin et al, 2014 , 2020 ; Bohm et al, 2017 ; Harris et al, 2017 ; Claeys et al, 2020 ), and one patient additionally manifested anhidrosis ( Ishitsuka et al, 2019 ). Histological examinations of the skin biopsy revealed an obstruction of the spiral duct in the eccrine gland, the acrosyringia, resulting in sweat retention.…”

“…In contrast, dominant STIM1 and ORAI1 gain-of-function (GoF) mutations inducing excessive Ca 2+ entry through SOCE over-activation were found in patients with tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) ( Bohm et al, 2013 ; Misceo et al, 2014 ; Morin et al, 2014 ; Nesin et al, 2014 ). TAM and STRMK form a clinical continuum characterized by progressive muscle weakness and myalgia predominantly affecting the lower limbs ( Chevessier et al, 2005 ), and most patients manifest a varying degree of additional multi-systemic signs as miosis, ichthyosis, short stature, hyposplenism, thrombocytopenia, and dyslexia ( Endo et al, 2015 ; Markello et al, 2015 ; Walter et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Noury et al, 2017 ; Bohm and Laporte, 2018 ; Morin et al, 2020 ). All GoF mutations are missense mutations affecting highly conserved amino acids in the Ca 2+ -binding EF hands (H72Q, N80T, G81D, D84G, D84E, S88G, L92V, L96V, Y98C, F108I, F108L; H109N, H109R, H109Y, I115F) ( Bohm et al, 2013 , 2014 ; Hedberg et al, 2014 ; Markello et al, 2015 ; Walter et al, 2015 ; Harris et al, 2017 ; Noury et al, 2017 ; Li et al, 2019 ; Claeys et al, 2020 ; Morin et al, 2020 ) or in the luminal coiled-coil domains of STIM1 (R304W, R304Q) ( Misceo et al, 2014 ; Morin et al, 2014 ; Nesin et al, 2014 ; Markello et al, 2015 ; Harris et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Sura et al, 2020 ), or in the ORAI1 transmembrane domains forming the channel pore or concentric rings surrounding the pore (G97C, G98S, V107M, L138F, T184M, P245L) ( Nesin et al, 2014 ; Endo et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Figure 1 ).…”

Calcium entry units (CEUs): perspectives in skeletal muscle function and disease

“…On the other hand, gain-of-function mutations in the same two genes have been linked to three different diseases: Stormorken and York Platelet syndromes Borsani et al 2018;Lacruz and Feske 2015;Nesin et al 2014;Markello et al 2015;Misceo et al 2014;Morin et al 2020) and to a rare form of myopathy known as tubular aggregate myopathy or TAM (Bohm et al 2013(Bohm et al , 2014Bulla et al 2019;Endo et al 2015;Okuma et al 2016;Walter et al 2015).…”