TY - JOUR
T1 - A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course
AU - Biancalana, Valérie
AU - Rendu, John
AU - Chaussenot, Annabelle
AU - Mecili, Helen
AU - Bieth, Eric
AU - Fradin, Mélanie
AU - Mercier, Sandra
AU - Michaud, Maud
AU - Nougues, Marie Christine
AU - Pasquier, Laurent
AU - Sacconi, Sabrina
AU - Romero, Norma B.
AU - Marcorelles, Pascale
AU - Authier, François Jérôme
AU - Gelot Bernabe, Antoinette
AU - Uro-Coste, Emmanuelle
AU - Cances, Claude
AU - Isidor, Bertrand
AU - Magot, Armelle
AU - Minot-Myhie, Marie Christine
AU - Péréon, Yann
AU - Perrier-Boeswillwald, Julie
AU - Bretaudeau, Gilles
AU - Dondaine, Nicolas
AU - Bouzenard, Alison
AU - Pizzimenti, Mégane
AU - Eymard, Bruno
AU - Ferreiro, Ana
AU - Laporte, Jocelyn
AU - Fauré, Julien
AU - Böhm, Johann
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-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.
AB - The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-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.
KW - Calcium
KW - Congenital myopathy
KW - Excitation–contraction coupling
KW - Muscle weakness
KW - Neuromuscular disorder
KW - Triad
UR - http://www.scopus.com/inward/record.url?scp=85115145527&partnerID=8YFLogxK
U2 - 10.1186/s40478-021-01254-y
DO - 10.1186/s40478-021-01254-y
M3 - Article
C2 - 34535181
AN - SCOPUS:85115145527
SN - 2051-5960
VL - 9
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 155
ER -