Identification of dominant negative effect of L522P mutation in the electrogenic Na+-HCO3 - Cotransporter NBCe1

Osamu Yamazaki, Hideomi Yamada, Masashi Suzuki, Shoko Horita, Ayumi Shirai, Motonobu Nakamura, Nobuhiko Satoh, Toshiro Fujita, George Seki

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Homozygous mutations in the electrogenic Na+-HCO3 - cotransporter NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as ocular abnormalities and migraine. Previously, the NBCe1 cytosolic mutant S982NfsX4 was shown to have a dominant negative effect by forming hetero-oligomer complexes with wild type (WT), which might be responsible for the occurrence of glaucoma and migraine in the heterozygous family members. In this study, we investigated whether the NBCe1 L522P mutant has a similar dominant negative effect. Functional analyses in Xenopus oocytes and HEK293 cells revealed that the L522P mutant had no transport activity due to defective membrane expression. Furthermore, when coexpressed with WT, L522P significantly reduced the transport activity of WT. In HEK293 cells, the cytosolic mutant L522P reduced the membrane expression of NBCe1 by forming hetero-oligomer complexes with WT. Among the artificial Leu522 mutants, L522I showed proper membrane expression and normal transport activity. However, the other mutants L522R, L522K, L522D, and L522E showed a predominant cytosolic retention. Moreover, L522R had a dominant negative effect, when coexpressed with WT. These results indicate that Leu 522 plays an important role in the structure and trafficking of NBCe1. They also suggest that the NBCe1 mutants retaining in cytoplasm may have the dominant negative effect in common, which may induce some clinical manifestations.

Original languageEnglish
Pages (from-to)1281-1291
Number of pages11
JournalPflugers Archiv European Journal of Physiology
Issue number9
Publication statusPublished - 2013 Sept
Externally publishedYes


  • Dominant negative effect
  • ER retention
  • Migraine
  • NBCe1
  • pRTA

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)


Dive into the research topics of 'Identification of dominant negative effect of L522P mutation in the electrogenic Na+-HCO3 - Cotransporter NBCe1'. Together they form a unique fingerprint.

Cite this