Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.
Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG)n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine.
Ophoff
R A
RA
MGC-Department of Human Genetics, Sylvius Laboratory, Leiden University, The Netherlands.
Terwindt
G M
GM
Vergouwe
M N
MN
van Eijk
R
R
Oefner
P J
PJ
Hoffman
S M
SM
Lamerdin
J E
JE
Mohrenweiser
H W
HW
Bulman
D E
DE
Ferrari
M
M
Haan
J
J
Lindhout
D
D
van Ommen
G J
GJ
Hofker
M H
MH
Ferrari
M D
MD
Frants
R R
RR
D001483:Base Sequence; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D013181:Cortical Spreading Depression / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006429:Hemiplegia / Q000209:etiology*; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000145:classification / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017384:Sequence Deletion
D015220:Calcium Channels; D009419:Nerve Tissue Proteins