Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine.
Homozygous mutations in SLC4A4, encoding the electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities. In this study, we report two sisters with pRTA, ocular abnormalities, and hemiplegic migraine. Genetic analysis ruled out pathological mutations in the known genes for familial hemiplegic migraine, but identified a homozygous 65-bp deletion (Delta65bp) in the C terminus of NBCe1, corresponding to the codon change S982NfsX4. Several heterozygous members of this family also presented glaucoma and migraine with or without aura. Despite the normal electrogenic activity in Xenopus oocytes, the Delta65bp mutant showed almost no transport activity due to a predominant cytosolic retention in mammalian cells. Furthermore, coexpression experiments uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1. Among other pRTA pedigrees with different NBCe1 mutations, we identified four additional homozygous patients with migraine. The immunohistological and functional analyses of these mutants demonstrate that the near total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.
Suzuki
Masashi
M
Department of Internal Medicine, University of Tokyo, Bunkyo-ku, Japan.
Van Paesschen
Wim
W
Stalmans
Ingeborg
I
Horita
Shoko
S
Yamada
Hideomi
H
Bergmans
Bruno A
BA
Legius
Eric
E
Riant
Florence
F
De Jonghe
Peter
P
Li
Yuehong
Y
Sekine
Takashi
T
Igarashi
Takashi
T
Fujimoto
Ichiro
I
Mikoshiba
Katsuhiko
K
Shimadzu
Mitsunobu
M
Shiohara
Masaaki
M
Braverman
Nancy
N
Al-Gazali
Lihadh
L
Fujita
Toshiro
T
Seki
George
G
D000818:Animals; D002460:Cell Line; D004285:Dogs; D005260:Female; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008881:Migraine Disorders / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics*; D014982:Xenopus laevis
C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters
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