| Abstract | A heterozygous Ile4898 to Thr (I4898T) mutation in the human type 1 ryanodine receptor/Ca(2+) release channel (RyR1) leads to a severe form of central core disease. We created a mouse line in which the corresponding Ryr1(I4895T) mutation was introduced by using a "knockin" 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(2+) release is absent, although retrograde enhancement of DHPR Ca(2+) conductance is retained. IT/IT mice, in which RyR1-mediated Ca(2+) 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(2+) signaling in mammalian embryogenesis. |
| Authors | Elena Zvaritch, Frederic Depreux, Natasha Kraeva, Ryan E Loy, Sanjeewa A Goonasekera, Simona Boncompagni, Simona Boncompagi, Alexander Kraev, Anthony O Gramolini, Robert T Dirksen, Clara Franzini-Armstrong, Christine E Seidman, J G Seidman, David H Maclennan
(Affiliation: Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College Street, Toronto, ON, Canada.)
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| Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 104
Issue 47
Pg. 18537-42
(Nov 20 2007)
ISSN: 1091-6490 United States |
| PMID | 18003898
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Ryanodine Receptor Calcium Release Channel
- Threonine
- Isoleucine
- Calcium
|
| Topics |
- Animals
- Animals, Newborn
- Calcium
(metabolism)
- Embryo, Mammalian
(embryology, metabolism)
- Fetal Growth Retardation
(genetics, metabolism, pathology)
- Gene Expression Regulation, Developmental
- Heart
(embryology)
- Homozygote
- Isoleucine
(genetics, metabolism)
- Mice
- Mice, Transgenic
- Microscopy, Electron
- Muscle Fibers
(metabolism, ultrastructure)
- Muscle, Skeletal
(embryology, metabolism)
- Mutation
(genetics)
- Ryanodine Receptor Calcium Release Channel
(genetics, metabolism)
- Skeleton
- Threonine
(genetics, metabolism)
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