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A calcium channel mutation causing hypokalemic periodic paralysis
K Jurkat-Rott1, F Lehmann-Horn, A Elbaz
1Department of Applied Physiology, University of Ulm, Germany.
Human Molecular Genetics
|August 1, 1994
Summary
A mutation in the dihydropyridine-receptor alpha 1-subunit gene causes hypokalemic periodic paralysis (HypoPP), a muscle disease. This genetic alteration affects muscle excitation-contraction coupling, leading to weakness.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- The dihydropyridine-receptor alpha 1-subunit gene is crucial for calcium channel function.
- Muscular dysgenesis in mice is linked to a deletion in this gene, causing neonatal death.
- Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant muscle disorder mapped to chromosome 1q31-32.
Purpose of the Study:
- To investigate the genetic basis of Hypokalemic Periodic Paralysis (HypoPP).
- To identify mutations in the dihydropyridine-receptor alpha 1-subunit gene associated with HypoPP.
Main Methods:
- Sequencing of cDNA from HypoPP patients.
- Restriction fragment analysis to detect mutations in affected families.
Main Results:
- A G-to-A base exchange at nucleotide 1583 was identified in two HypoPP patients, predicting a histidine to arginine substitution at position 528.
- This mutation affects the voltage-sensing IIS4 transmembrane segment of the dihydropyridine-receptor alpha 1-subunit.
- The identified mutation was present in affected members of 9 out of 25 HypoPP families.
Conclusions:
- The dihydropyridine-receptor alpha 1-subunit mutation is a cause of Hypokalemic Periodic Paralysis (HypoPP).
- Altered excitation-contraction coupling due to this mutation likely explains the muscle weakness observed in HypoPP patients.