title: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis.
abstract: Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant skeletal muscle disorder manifested by episodic weakness associated with low serum potassium. Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31-q32 near a dihydropyridine (DHP) receptor gene. This receptor functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner. We have characterized patient-specific DHP receptor mutations in 11 probands of 33 independent hypoKPP kindreds that occur at one of two adjacent nucleotides within the same codon and predict substitution of a highly conserved arginine in the S4 segment of domain 4 with either histidine or glycine. In one kindred, the mutation arose de novo. Taken together, these data establish this DHP receptor as the hypoKPP gene. We are unaware of any other human diseases presently known to result from DHP receptor mutations.
authors.affiliation: Department of Neurology, University of Utah Health Sciences Center, Salt Lake City 84132.
authors.forename: L J
authors.initials: LJ
authors.lastname: Ptácek
authors.forename: R
authors.initials: R
authors.lastname: Tawil
authors.forename: R C
authors.initials: RC
authors.lastname: Griggs
authors.forename: A G
authors.initials: AG
authors.lastname: Engel
authors.forename: R B
authors.initials: RB
authors.lastname: Layzer
authors.forename: H
authors.initials: H
authors.lastname: Kwieciński
authors.forename: P G
authors.initials: PG
authors.lastname: McManis
authors.forename: L
authors.initials: L
authors.lastname: Santiago
authors.forename: M
authors.initials: M
authors.lastname: Moore
authors.forename: G
authors.initials: G
authors.lastname: Fouad
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type; D002878:Chromosomes, Human, Pair 1; D004247:DNA; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010243:Paralysis / Q000235:genetics*; D010375:Pedigree; D010507:Periodicity; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011817:Rabbits; D017386:Sequence Homology, Amino Acid
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D004247:DNA