Chiara Ticci1,2, Denise Cassandrini1, Anna Rubegni1, Beatrice Riva3, Gaetano Vattemi4, Sabrina Matà5, Giulia Ricci6, Jacopo Baldacci1,7, Valeria Guglielmi4, Antonio Di Muzio8, Alessandro Malandrini9, Paola Tonin4, Gabriele Siciliano6, Antonio Federico9, Armando A Genazzani3, Filippo M Santorelli1, Luciano Merlini10. 1. IRCCS Fondazione Stella Maris, Molecular Medicine Laboratory, Pisa, Italy. 2. AOU Meyer, Florence, Italy. 3. Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy. 4. Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. 5. Careggi University Hospital, Neurology Unit, Florence, Italy. 6. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 7. Kode s.r.l., Pisa, Italy. 8. Department of Neurology, SS Annunziata Hospital, Chieti, Italy. 9. Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy. 10. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Abstract
INTRODUCTION/AIMS: Stromal interaction molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1. METHODS: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. RESULTS: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients. DISCUSSION: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.
INTRODUCTION/AIMS: Stromal interaction molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1. METHODS: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. RESULTS: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients. DISCUSSION: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.
Authors: Eduardo de la Fuente-Munoz; Ana Van Den Rym; Blanca García-Solis; Juliana Ochoa Grullón; Kissy Guevara-Hoyer; Miguel Fernández-Arquero; Lucía Galán Dávila; Jorge Matías-Guiú; Silvia Sánchez-Ramón; Rebeca Pérez de Diego Journal: Front Immunol Date: 2022-06-24 Impact factor: 8.786