{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:15:43Z","timestamp":1791029743831,"version":"4.1.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"47","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,11,20]]},"abstract":"<jats:p>\n                    A heterozygous Ile4898 to Thr (I4898T) mutation in the human type 1 ryanodine receptor\/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release channel (RyR1) leads to a severe form of central core disease. We created a mouse line in which the corresponding\n                    <jats:italic>Ryr1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>I4895T<\/jats:italic>\n                    <\/jats:sup>\n                    mutation was introduced by using a \u201cknockin\u201d protocol. The heterozygote does not exhibit an overt disease phenotype, but homozygous (IT\/IT) mice are paralyzed and die perinatally, apparently because of asphyxia. Histological analysis shows that IT\/IT mice have greatly reduced and amorphous skeletal muscle. Myotubes are small, nuclei remain central, myofibrils are disarranged, and no cross striation is obvious. Many areas indicate probable degeneration, with shortened myotubes containing central stacks of pyknotic nuclei. Other manifestations of a delay in completion of late stages of embryogenesis include growth retardation and marked delay in ossification, dermatogenesis, and cardiovascular development. Electron microscopy of IT\/IT muscle demonstrates appropriate targeting and positioning of RyR1 at triad junctions and a normal organization of dihydropyridine receptor (DHPR) complexes into RyR1-associated tetrads. Functional studies carried out in cultured IT\/IT myotubes show that ligand-induced and DHPR-activated RyR1 Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release is absent, although retrograde enhancement of DHPR Ca\n                    <jats:sup>2+<\/jats:sup>\n                    conductance is retained. IT\/IT mice, in which RyR1-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release is abolished without altering the formation of the junctional DHPR-RyR1 macromolecular complex, provide a valuable model for elucidation of the role of RyR1-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling in mammalian embryogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0709312104","type":"journal-article","created":{"date-parts":[[2007,11,14]],"date-time":"2007-11-14T21:19:01Z","timestamp":1195075141000},"page":"18537-18542","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":79,"title":["An\n                    <i>Ryr1<\/i>\n                    <sup>\n                      <i>I4895T<\/i>\n                    <\/sup>\n                    mutation abolishes Ca\n                    <sup>2+<\/sup>\n                    release channel function and delays development in homozygous offspring of a mutant mouse line"],"prefix":"10.1073","volume":"104","author":[{"given":"Elena","family":"Zvaritch","sequence":"first","affiliation":[{"name":"*Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada M5G 1L6;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Depreux","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Kraeva","sequence":"additional","affiliation":[{"name":"*Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada M5G 1L6;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan E.","family":"Loy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeewa A.","family":"Goonasekera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Boncompagni","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA19104-6058;"},{"name":"Center for Research on Aging, Universit\u00e0 G. d'Annunzio, Chieti CH I-66013, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kraev","sequence":"additional","affiliation":[{"name":"*Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada M5G 1L6;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony O.","family":"Gramolini","sequence":"additional","affiliation":[{"name":"*Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada M5G 1L6;"},{"name":"Department of Physiology, University of Toronto, Toronto, ON, Canada M55 1A8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Franzini-Armstrong","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA19104-6058;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine E.","family":"Seidman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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