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- Title
Identification of dominant negative effect of L522P mutation in the electrogenic Na-HCO cotransporter NBCe1.
- Authors
Yamazaki, Osamu; Yamada, Hideomi; Suzuki, Masashi; Horita, Shoko; Shirai, Ayumi; Nakamura, Motonobu; Satoh, Nobuhiko; Fujita, Toshiro; Seki, George
- Abstract
Homozygous mutations in the electrogenic Na-HCO 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 Leu 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 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.
- Subjects
GENETIC mutation; CARRIER proteins; ACIDOSIS; KIDNEY tubules; POLYMERS; EYE diseases; BIOLOGICAL membranes
- Publication
Pflügers Archiv: European Journal of Physiology, 2013, Vol 465, Issue 9, p1281
- ISSN
0031-6768
- Publication type
Article
- DOI
10.1007/s00424-013-1277-1