PNAS：发现偏头疼相关基因NBCe1

2010/08/30 05:39:43

日本研究人员在24日的美国《国家科学院学报》网络版上发表论文说，他们发现一个与偏头疼有关的基因。该成果有助于了解偏头疼的发病机制，并为以该基因为靶向开发治疗药物奠定了基础。

东京大学讲师关常司等人在研究中发现，在NBCe1基因异常的人中，很多都有偏头疼症状。进一步的细胞培养发现，如果“NBCe1”基因出现异常，氢离子浓度的调节就会紊乱，使神经细胞异常兴奋，从而导致偏头疼。

偏头疼的具体发病机制尚属未知。但医学界普遍认为，神经细胞的过度兴奋是导致偏头疼的重要原因。

PNAS doi: 10.1073/pnas.1008705107

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

Masashi Suzukia, Wim Van Paesschenb, Ingeborg Stalmansc, Shoko Horitaa, Hideomi Yamadaa, Bruno A. Bergmansb, Eric Legiusd, Florence Riante, Peter De Jonghef, Yuehong Lia, Takashi Sekineg, Takashi Igarashih, Ichiro Fujimotoi, Katsuhiko Mikoshibaj, Mitsunobu Shimadzuk, Masaaki Shioharal, Nancy Bravermanm, Lihadh Al-Gazalin, Toshiro Fujitaa, and George Sekia

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, 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.