Defective membrane expression of the Na+-HCO3 - cotransporter NBCe1 is associated with familial migraine

Masashi Suzuki, Wim Van Paesschen, Ingeborg Stalmans, Shoko Horita, Hideomi Yamada, Bruno A. Bergmans, Eric Legius, Florence Riant, Peter De Jonghe, Yuehong Li, Takashi Sekine, Takashi Igarashi, Ichiro Fujimoto, Katsuhiko Mikoshiba, Mitsunobu Shimadzu, Masaaki Shiohara, Nancy Braverman, Lihadh Al-Gazali, Toshiro Fujita, George Seki

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)


Homozygous mutations in SLC4A4, encoding the electrogenic Na +-HCO3- 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 (Δ65bp) 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 Δ65bp 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,weidentified 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.

Original languageEnglish
Pages (from-to)15963-15968
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
Publication statusPublished - Sept 7 2010


  • Dominant negative effect
  • Epilepsy
  • Glaucoma
  • Proximal renal tubular acidosis
  • SLC4A4

ASJC Scopus subject areas

  • General


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