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Open Access 01-11-2018 | Original Communication

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

Authors: Joshua J. Todd, Vatsala Sagar, Tokunbor A. Lawal, Carolyn Allen, Muslima S. Razaqyar, Monique S. Shelton, Irene C. Chrismer, Xuemin Zhang, Mary M. Cosgrove, Anna Kuo, Ruhi Vasavada, Minal S. Jain, Melissa Waite, Dinusha Rajapakse, Jessica W. Witherspoon, Graeme Wistow, Katherine G. Meilleur

Published in: Journal of Neurology | Issue 11/2018

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 apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.

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Title: Correlation of phenotype with genotype and protein structure in RYR1-related disorders
Authors: Joshua J. Todd
Vatsala Sagar
Tokunbor A. Lawal
Carolyn Allen
Muslima S. Razaqyar
Monique S. Shelton
Irene C. Chrismer
Xuemin Zhang
Mary M. Cosgrove
Anna Kuo
Ruhi Vasavada
Minal S. Jain
Melissa Waite
Dinusha Rajapakse
Jessica W. Witherspoon
Graeme Wistow
Katherine G. Meilleur
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 11/2018
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-018-9033-2

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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