{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:15:56Z","timestamp":1791342956186,"version":"4.3.1"},"reference-count":44,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2010,9,13]],"date-time":"2010-09-13T00:00:00Z","timestamp":1284336000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2010,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in\n                      <jats:italic>MTM1, DNM2,<\/jats:italic>\n                      and\n                      <jats:italic>BIN1<\/jats:italic>\n                      but many cases remain genetically unresolved.\n                      <jats:italic>RYR1<\/jats:italic>\n                      encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether\n                      <jats:italic>RYR1<\/jats:italic>\n                      mutations cause CNM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We sequenced the entire\n                      <jats:italic>RYR1<\/jats:italic>\n                      coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for\n                      <jats:italic>RYR1<\/jats:italic>\n                      missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The high incidence in South African patients (n = 12\/14) in conjunction with recurrent\n                      <jats:italic>RYR1<\/jats:italic>\n                      mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Our findings expand the range of\n                      <jats:italic>RYR1<\/jats:italic>\n                      \u2010related phenotypes and suggest\n                      <jats:italic>RYR1<\/jats:italic>\n                      mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X\u2010linked CNM, these findings indicate disturbed assembly and\/or malfunction of the excitation\u2010contraction machinery as a key mechanism in CNM and related myopathies.ANN NEUROL 2010\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.22119","type":"journal-article","created":{"date-parts":[[2010,9,13]],"date-time":"2010-09-13T13:32:10Z","timestamp":1284384730000},"page":"717-726","source":"Crossref","is-referenced-by-count":266,"title":["<i>RYR1<\/i>\n                    mutations are a common cause of congenital myopathies with central 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