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XB-ART-41959
Proc Natl Acad Sci U S A 2010 Sep 07;10736:15963-8. doi: 10.1073/pnas.1008705107.
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Defective membrane expression of the Na(+)-HCO(3)(-) cotransporter NBCe1 is associated with familial migraine.

Suzuki M , Van Paesschen W , Stalmans I , Horita S , Yamada H , Bergmans BA , Legius E , Riant F , De Jonghe P , Li Y , Sekine T , Igarashi T , Fujimoto I , Mikoshiba K , Shimadzu M , Shiohara M , Braverman N , Al-Gazali L , Fujita T , Seki G .


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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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Species referenced: Xenopus laevis
Genes referenced: aurka slc4a4

References [+] :
Abuladze, Structural organization of the human NBC1 gene: kNBC1 is transcribed from an alternative promoter in intron 3. 2000, Pubmed