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A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course

Valérie Biancalana 1, 2 John Rendu 3, 4 Annabelle Chaussenot 5 Helen Mecili 6 Eric Bieth 7 Mélanie Fradin 8, 9 Sandra Mercier 10, 11 Maud Michaud 6 Marie-Christine Nougues 12 Laurent Pasquier 8, 9 Sabrina Sacconi 13, 14 Norma Romero 15, 16 Pascale Marcorelles 17, 18 François Jérôme Authier 19, 20 Antoinette Gelot Bernabe 12, 21 Emmanuelle Uro-Coste 22 Claude Cances 22 Bertrand Isidor 10, 11 Armelle Magot 10, 11 Marie-Christine Minot-Myhie 23 Yann Péréon 10, 11 Julie Perrier-Boeswillwald 11 Gilles Bretaudeau 23 Nicolas Dondaine 2 Alison Bouzenard 1 Mégane Pizzimenti 1 Bruno Eymard 15, 16 Ana Ferreiro 15, 16, 24 Jocelyn Laporte 1 Julien Fauré 3, 25 Johann Böhm 1 
Abstract : Abstract The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca 2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca 2+ -dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1 -related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1 -typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
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Submitted on : Friday, March 18, 2022 - 1:14:06 PM
Last modification on : Friday, August 5, 2022 - 12:01:42 PM

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Valérie Biancalana, John Rendu, Annabelle Chaussenot, Helen Mecili, Eric Bieth, et al.. A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course. Acta Neuropathologica Communications, BioMed Central part of Springer Science, 2021, 9 (1), pp.155. ⟨10.1186/s40478-021-01254-y⟩. ⟨hal-03613310⟩



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