PMID- 10097181
OWN - NLM
STAT- MEDLINE
DCOM- 19990512
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 7
DP  - 1999 Mar 30
TI  - A mutation in the transmembrane/luminal domain of the ryanodine receptor is 
      associated with abnormal Ca2+ release channel function and severe central core 
      disease.
PG  - 4164-9
AB  - Central core disease is a rare, nonprogressive myopathy that is characterized by 
      hypotonia and proximal muscle weakness. In a large Mexican kindred with an 
      unusually severe and highly penetrant form of the disorder, DNA sequencing 
      identified an I4898T mutation in the C-terminal transmembrane/luminal region of 
      the RyR1 protein that constitutes the skeletal muscle ryanodine receptor. All 
      previously reported RYR1 mutations are located either in the cytoplasmic N 
      terminus or in a central cytoplasmic region of the 5,038-aa protein. The I4898T 
      mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. 
      The response of the mutant RyR1 Ca2+ channel to the agonists halothane and 
      caffeine in a Ca2+ photometry assay was completely abolished. Coexpression of 
      normal and mutant RYR1 cDNAs in a 1:1 ratio, however, produced RyR1 channels with 
      normal halothane and caffeine sensitivities, but maximal levels of Ca2+ release 
      were reduced by 67%. [3H]Ryanodine binding indicated that the heterozygous 
      channel is activated by Ca2+ concentrations 4-fold lower than normal. Single-cell 
      analysis of cotransfected cells showed a significantly increased resting 
      cytoplasmic Ca2+ level and a significantly reduced luminal Ca2+ level. These data 
      are indicative of a leaky channel, possibly caused by a reduction in the Ca2+ 
      concentration required for channel activation. Comparison with two other 
      coexpressed mutant/normal channels suggests that the I4898T mutation produces one 
      of the most abnormal RyR1 channels yet investigated, and this level of 
      abnormality is reflected in the severe and penetrant phenotype of affected 
      central core disease individuals.
FAU - Lynch, P J
AU  - Lynch PJ
AD  - Department of Biochemistry, University College Cork, Ireland.
FAU - Tong, J
AU  - Tong J
FAU - Lehane, M
AU  - Lehane M
FAU - Mallet, A
AU  - Mallet A
FAU - Giblin, L
AU  - Giblin L
FAU - Heffron, J J
AU  - Heffron JJ
FAU - Vaughan, P
AU  - Vaughan P
FAU - Zafra, G
AU  - Zafra G
FAU - MacLennan, D H
AU  - MacLennan DH
FAU - McCarthy, T V
AU  - McCarthy TV
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA, Complementary)
RN  - 0 (Genetic Markers)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - 3G6A5W338E (Caffeine)
RN  - SY7Q814VUP (Calcium)
RN  - UQT9G45D1P (Halothane)
SB  - IM
CIN - Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3345-7. PMID: 10097041
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Caffeine/pharmacology
MH  - Calcium/metabolism
MH  - Cell Line
MH  - Chromosome Mapping
MH  - Cloning, Organism
MH  - DNA, Complementary
MH  - Female
MH  - Genetic Markers
MH  - Genotype
MH  - Halothane/pharmacology
MH  - Humans
MH  - Male
MH  - Mexico
MH  - Mutagenesis, Site-Directed
MH  - Myopathies, Nemaline/*genetics/physiopathology
MH  - Pedigree
MH  - *Point Mutation
MH  - *Polymorphism, Genetic
MH  - Rabbits
MH  - Recombinant Proteins/drug effects/metabolism
MH  - Ryanodine Receptor Calcium Release Channel/drug effects/*genetics/*physiology
MH  - Transfection
PMC - PMC22438
EDAT- 1999/03/31 00:00
MHDA- 1999/03/31 00:01
CRDT- 1999/03/31 00:00
PHST- 1999/03/31 00:00 [pubmed]
PHST- 1999/03/31 00:01 [medline]
PHST- 1999/03/31 00:00 [entrez]
AID - 4070 [pii]
AID - 10.1073/pnas.96.7.4164 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4164-9. doi: 10.1073/pnas.96.7.4164.