title: Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis.
abstract: We have identified a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 (NBC1) in a patient with isolated proximal renal tubular acidosis (pRTA). To specifically address the pathogenesis of this mutation, we created NBC1 W516X knock-in mice to match the patient's abnormalities. The expression of NBC1 mRNA and protein in the kidneys of NBC1(W516X/W516X) mice were virtually absent, indicating that nonsense-mediated mRNA decay (NMD) is involved in the defective transcription and translation of this mutation. These mice not only recapitulated the phenotypes of this patient with growth retardation, pRTA, and ocular abnormalities, but also showed anemia, volume depletion, prerenal azotemia, and several organ abnormalities, culminating in dehydration and renal failure with early lethality before weaning. In isolated renal proximal tubules, both NBC1 activity and the rate of bicarbonate absorption were markedly reduced. Unexpectedly, there was no compensatory increase in mRNA of distal acid/base transporters. Sodium bicarbonate but not saline administration to these mutant mice markedly prolonged their survival, decreased their protein catabolism and attenuated organ abnormalities. The prolonged survival time uncovered the development of corneal opacities due to corneal edema. Thus, NBC1(W516X/W516X) mice with pRTA represent an animal model for metabolic acidosis and may be useful for testing therapeutic inhibition of NMD in vivo.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lo
authors.forename: Sung-Sun
authors.initials: SS
authors.lastname: Yang
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.forename: Hideomi
authors.initials: H
authors.lastname: Yamada
authors.forename: Shoko
authors.initials: S
authors.lastname: Horita
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamazaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Usui
authors.forename: Jeng-Daw
authors.initials: JD
authors.lastname: Tsai
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000138:Acidosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000141:Acidosis, Renal Tubular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000367:Age Factors; D000375:Aging; D000704:Analysis of Variance; D000740:Anemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism; D018389:Codon, Nonsense; D003318:Corneal Opacity / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D017693:Sodium Bicarbonate / Q000008:administration & dosage / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D001639:Bicarbonates; D018389:Codon, Nonsense; D012333:RNA, Messenger; C498898:SLC4A4 protein, human; C498899:Slc4a4 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D017693:Sodium Bicarbonate