Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Journal of Neurology
Joshua J ToddKatherine G Meilleur

Abstract

Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most ap...Continue Reading

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Citations

Jan 17, 2020·Neurology·Joshua J ToddKatherine G Meilleur
Apr 3, 2020·Acta Neuropathologica·Alexander KushnirAndrew R Marks
Jul 14, 2020·Expert Review of Molecular Diagnostics·Vinojini VivekanandamMichael G Hanna
Nov 9, 2018·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Tokunbor A LawalKatherine G Meilleur
Nov 11, 2020·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Marcin M MachnickiGaetano Vattemi
Dec 3, 2020·Practical Neurology·Waqar WaheedRup Tandan
Mar 2, 2021·Journal of Neuromuscular Diseases·Tokunbor A LawalKatherine G Meilleur
Sep 19, 2021·Acta Neuropathologica Communications·Valérie BiancalanaJohann Böhm

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Methods Mentioned

BETA
biopsy

Clinical Trials Mentioned

NCT02362425

Software Mentioned

CoughAssist
Pymol
BiPAP
Statistical Package for the Social Sciences
Alamut Visual
BreezeSuite

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