A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course.
Acta Neuropathol Commun
; 9(1): 155, 2021 09 17.
Article
en En
| MEDLINE
| ID: mdl-34535181
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Progresión de la Enfermedad
/
Canal Liberador de Calcio Receptor de Rianodina
/
Hipotonía Muscular
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Adolescent
/
Adult
/
Aged
/
Child, preschool
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Acta Neuropathol Commun
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia