title: Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Tokyo, Bunkyo-ku, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Wim
authors.initials: W
authors.lastname: Van Paesschen
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Stalmans
authors.forename: Shoko
authors.initials: S
authors.lastname: Horita
authors.forename: Hideomi
authors.initials: H
authors.lastname: Yamada
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Bergmans
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.forename: Florence
authors.initials: F
authors.lastname: Riant
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Li
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekine
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Fujimoto
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Shimadzu
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiohara
authors.forename: Nancy
authors.initials: N
authors.lastname: Braverman
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: George
authors.initials: G
authors.lastname: Seki
mesh_terms: 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
chemical_list: C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters
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