Defective Membrane Expression of the Na(+)-HCO(3)(-) Cotransporter NBCe1 is Associated with Familial Migraine

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Aug 28

PMID 20798035

Citations 82

Authors

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

Affiliations

Soon will be listed here.

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.

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