Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations.

Abstract

Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.

• Authors: Jan Eckhardt, Christoph Bachmann, Sofia Benucci, Moran Elbaz, Alexis Ruiz, Francesco Zorzato, Susan Treves
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 29 Issue 8 Pg. 1330-1339 (05 28 2020) ISSN: 1460-2083 [Electronic] England
• PMID: 32242214 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Ryanodine Receptor Calcium Release Channel
• ryanodine receptor 1, mouse
• Myosin Heavy Chains

Topics

• Animals
• Disease Models, Animal
• Heterozygote
• Humans
• Mice
• Muscle Weakness (genetics, pathology)
• Muscle, Skeletal (metabolism, pathology)
• Mutation (genetics)
• Myosin Heavy Chains (genetics)
• Myotonia Congenita (genetics, pathology)
• Oculomotor Muscles (metabolism, pathology)
• Phenotype
• Ryanodine Receptor Calcium Release Channel (genetics)