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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.<\/jats:p><jats:p>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.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa056","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T19:19:09Z","timestamp":1585682349000},"page":"1330-1339","source":"Crossref","is-referenced-by-count":7,"title":["Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations"],"prefix":"10.1093","volume":"29","author":[{"given":"Jan","family":"Eckhardt","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Bachmann","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Benucci","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moran","family":"Elbaz","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Ruiz","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Zorzato","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"},{"name":"Department of Life Science and Biotechnology, University of Ferrara, 44100 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Treves","sequence":"first","affiliation":[{"name":"Departments of Biomedicine, Basel University Hospital, 4031 Basel, Switzerland"},{"name":"Department of Life Science and Biotechnology, University of Ferrara, 44100 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"2020052807295461600_ref1","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1152\/physrev.1991.71.3.849","article-title":"Voltage sensor of excitation-contraction coupling in skeletal muscle","volume":"71","author":"Rios","year":"1991","journal-title":"Physiol. 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