Title: Defective membrane expression of the Na+-HCO3- cotransporter NBCe1 is associated with familial migraine
Authors: Suzuki, Masashi ×
Van Paesschen, Wim
Stalmans, Ingeborg
Horita, Shoko
Yamada, Hideomi
Bergmans, Bruno A
Legius, Eric
Riant, Florence
De Jonghe, Peter
Sekine, Takashi
Igarashi, Takashi
Fujimoto, Ichiro
Mikoshiba, Katsuhiko
Shimadzu, Mitsunobu
Shiohara, Masaaki
Braverman, Nancy
Al-Gazali, Lihadh
Fujita, Toshiro
Seki, George #
Issue Date: Sep-2010
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:107 issue:36 pages:15963-15968
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.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Research Group Experimental Neurology
Research Group Ophthalmology
Laboratory for Epilepsy Research
× corresponding author
# (joint) last author

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