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Functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central core disease, expressed in immortalized lymphocytes
- Source :
- Biochemical Journal, Biochemical Journal, Portland Press, 2006, 395 (2), pp.259-66. ⟨10.1042/BJ20051282⟩, Biochemical Journal, 2006, 395 (2), pp.259-66. ⟨10.1042/BJ20051282⟩
- Publication Year :
- 2006
- Publisher :
- Portland Press Ltd., 2006.
-
Abstract
- International audience; More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and central core disease, and with recessive forms of multi-minicore disease. Studies on the functional effects of pathogenic dominant mutations have shown that they mostly affect intracellular Ca2+ homoeostasis, either by rendering the channel hypersensitive to activation (malignant hyperthermia) or by altering the amount of Ca2+ released subsequent to physiological or pharmacological activation (central core disease). In the present paper, we show, for the first time, data on the functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-minicore disease. We studied the intracellular Ca2+ homoeostasis of EBV (Epstein-Barr virus)-transformed lymphoblastoid cells from the affected patients, their healthy relatives and control individuals. Our results show that the P3527S substitution in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-chloro-m-cresol and caffeine, but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on either the size of the intracellular Ca2+ stores, or on the amount of Ca2+ released after ryanodine receptor activation; however, both the P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration.
- Subjects :
- Herpesvirus 4, Human
DNA Mutational Analysis
[SDV.GEN] Life Sciences [q-bio]/Genetics
MESH: Thapsigargin
Biochemistry
MESH: Caffeine
MESH: Ryanodine Receptor Calcium Release Channel
MESH: Dose-Response Relationship, Drug
Calcium channel
Central core disease
Lymphoblastoid cell line
Malignant hyperthermia
Multi-minicore disease
Ryanodine receptor
Cresols
0302 clinical medicine
Lymphocytes
Myopathy, Central Core
MESH: DNA Mutational Analysis
Receptor
Cells, Cultured
chemistry.chemical_classification
0303 health sciences
MESH: Drug Screening Assays, Antitumor
MESH: Amino Acid Substitution
MESH: Case-Control Studies
3. Good health
Amino acid
MESH: Cresols
medicine.anatomical_structure
Thapsigargin
Intracellular
MESH: Cells, Cultured
Research Article
medicine.medical_specialty
MESH: Mutation
MESH: Myopathy, Central Core
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Biology
MESH: Calcium Signaling
03 medical and health sciences
Caffeine
Internal medicine
medicine
Humans
Calcium Signaling
Molecular Biology
030304 developmental biology
[SDV.GEN]Life Sciences [q-bio]/Genetics
MESH: Humans
Dose-Response Relationship, Drug
Skeletal muscle
MESH: Herpesvirus 4, Human
Ryanodine Receptor Calcium Release Channel
Cell Biology
medicine.disease
Molecular biology
Endocrinology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Amino Acid Substitution
chemistry
Case-Control Studies
Mutation
MESH: Lymphocytes
Drug Screening Assays, Antitumor
030217 neurology & neurosurgery
Homeostasis
Subjects
Details
- ISSN :
- 14708728 and 02646021
- Volume :
- 395
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....95f67a98c1f5a74460abf4d0c5582a02