Electrolyte Blood Press.  2010 Jun;8(1):25-31. 10.5049/EBP.2010.8.1.25.

Molecular Approach for Distal Renal Tubular Acidosis Associated AE1 Mutations

• Vasuvattakul S

• KMID: 1462999
• DOI: http://doi.org/10.5049/EBP.2010.8.1.25

Abstract

The molecular approaches to distal renal tubular acidosis (dRTA) associated AE1 mutations lead us to understand the genetic and pathophysiological aspects of the acidification defects. An unanticipated high value of the urine-blood (U-B) PCO2 after NaHCO3 loading observed in a case of dRTA and southeast Asian ovalocytosis (SAO) might be from a mistarget of the AE1 to the luminal membrane of type A intercalated cells. The mutations of the AE1 gene resulted in SAO and also affected renal acidification function. Notwithstanding, after the NH4Cl loading in 20 individuals with SAO, the acidification in the distal nephron was normal. The presence of both SAO and G701D mutations of AE1 gene would explain the abnormal urinary acidification in the patients with the compound heterozogosity. In terms of the effect of the mutations on trafficking of AE1, truncated kidney isoform (kAE1) of wild-type showed a 'dominant-positive effect' in rescuing the recessive mutant kAE1 (S773P or G701D) trafficking to the plasma membrane, in contrast with the dominant mutant kAE1 (R589H) resulting in a 'dominant-negative effect' when heterodimerized with the wild-type kAE1. It is notable that the dominant mutants kAE1 (R901X or G609R) expression in MDCK cells clearly results in aberrant surface expression with some mutant protein appearing at the apical membrane. These might result in net bicarbonate secretion and increasing U-B PCO2 in the distal nephron. The molecular physiological and genetic approaches have permitted identification of the molecular defects, predominantly in transporter proteins, and should in turn prompt development of novel therapeutic strategies.

Keyword

acidosis, renal tubular; southeast Asian ovalocytosis; chloridebicarbonate antiporters; anion exchange protein 1, erythrocyte; urine-blood PCO2; compound heterozygosity; trafficking defect

MeSH Terms

Acidosis, Renal Tubular
Anion Exchange Protein 1, Erythrocyte
Asian Continental Ancestry Group
Cell Membrane
Humans
Kidney
Madin Darby Canine Kidney Cells
Membranes
Mutant Proteins
Nephrons
Organometallic Compounds
Phenobarbital
Proteins
Anion Exchange Protein 1, Erythrocyte
Mutant Proteins
Organometallic Compounds
Phenobarbital
Proteins

Reference

1. Karet FE, Finberg KE, Nelson RD, et al. Mutations in the gene encoding B1 subunit of H⁺-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet. 1999; 21:84–90. PMID: 9916796.

2. Nilwarangkur S, Nimmannit S, Chaovakul V, et al. Endemic primary distal renal tubular acidosis in Thailand. Q J Med. 1990; 74:289–301. PMID: 2385736.

3. Halperin ML, Goldstein MB, Richardson RM, Stinebaugh BJ. Distal renal tubular acidosis syndromes: a pathophysiological approach. Am J Nephrol. 1985; 5:1–8. PMID: 3970076.

4. Nimmannit S, Malasit P, Susaengrat W, et al. Prevalence of endemic distal renal tubular acidosis and renal stone in the northeast of Thailand. Nephron. 1996; 72:604–610. PMID: 8730429.

5. Vasuvattakul S, Nimmannit S, Chaovakul V, et al. The spectrum of endemic renal tubular acidosis in the northeast of Thailand. Nephron. 1996; 74:541–547. PMID: 8938678.

6. Sritippayawan S, Sumboonnanonda A, Vasuvattakul S, et al. Novel compound heterozygous SLC4A1 mutations in Thai patients with autosomal recessive distal renal tubular acidosis. Am J Kidney Dis. 2004; 44:64–70. PMID: 15211439.

7. Yenchitsomanus PT, Vasuvattakul S, Kirdpon S, et al. Autosomal recessive distal renal tubular acidosis caused by G701D mutation of anion exchanger 1 gene. Am J Kidney Dis. 2002; 40:21–29. PMID: 12087557.

8. Tanphaichitr VS, Sumboonnanonda A, Ideguchi H, et al. Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A. J Clin Invest. 1998; 102:2173–2179. PMID: 9854053.

9. Karet FE, Gainza FJ, Gyory AZ, et al. Mutations in the chloridebicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc Natl Acad Sci U S A. 1998; 95:6337–6342. PMID: 9600966.

10. Jarolim P, Shayakul C, Prabakaran D, et al. Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl^-/HCO₃^- exchanger. J Biol Chem. 1998; 273:6380–6388. PMID: 9497368.

11. Bruce LJ, Cope DL, Jones GK, et al. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. J Clin Invest. 1997; 100:1693–1707. PMID: 9312167.

12. Pereira PC, Miranda DM, Oliveira EA, Silva AC. Molecular pathophysiology of renal tubular acidosis. Curr Genomics. 2009; 10:51–59. PMID: 19721811.

13. Fry AC, Karet FE. Inherited renal acidoses. Physiology (Bethesda). 2007; 22:202–211. PMID: 17557941.

14. Kaitwatcharachai C, Vasuvattakul S, Yenchitsomanus P, et al. Distal renal tubular acidosis and high urine carbon dioxide tension in a patient with southeast Asian ovalocytosis. Am J Kidney Dis. 1999; 33:1147–1152. PMID: 10352205.

15. Kamel KS, Briceno LF, Sanchez MI, et al. A new classification for renal defects in net acid excretion. Am J Kidney Dis. 1997; 29:136–146. PMID: 9002543.

16. DuBose TD Jr, Caflisch CR. Validation of the difference in urine and blood carbon dioxide tension during bicarbonate loading as an index of distal nephron acidification in experimental models of distal renal tubular acidosis. J Clin Invest. 1985; 75:1116–1123. PMID: 3921566.

17. Halperin ML, Goldstein MB, Haig A, Johnson MD, Stinebaugh BJ. Studies on the pathogenesis of type I (distal) renal tubular acidosis as revealed by the urinary PCO2 tensions. J Clin Invest. 1974; 53:669–677. PMID: 4812435.

18. Rysava R, Tesar V, Jirsa M Jr, Brabec V, Jarolim P. Incomplete distal renal tubular acidosis coinherited with a mutation in the band 3 (AE1) gene. Nephrol Dial Transplant. 1997; 12:1869–1873. PMID: 9306337.

19. Lie-Injo LE FA, Bolton JM, Gilman RH. Hereditary elliptocytosis in Malayan aborigines. Acta Haematol. 1972; 47:210–216. PMID: 4625303.

20. Jarolim P, Palek J, Amato D, et al. Deletion in erythrocyte band 3 gene in malaria-resistant Southeast Asian ovalocytosis. Proc Natl Acad Sci U S A. 1991; 88:11022–11026. PMID: 1722314.

21. Liu SC, Zhai S, Palek J, et al. Molecular defect of the band 3 protein in southeast Asian ovalocytosis. N Engl J Med. 1990; 323:1530–1538. PMID: 2146504.

22. Wagner CA, Kovacikova J, Stehberger PA, Winter C, Benabbas C, Mohebbi N. Renal acid-base transport: old and new players. Nephron Physiol. 2006; 103:p1–p6. PMID: 16352913.

23. Alper SL. Molecular physiology of SLC4 anion exchangers. Exp Physiol. 2006; 91:153–161. PMID: 16239253.

24. Vasuvattakul S, Yenchitsomanus PT, Vachuanichsanong P, et al. Autosomal recessive distal renal tubular acidosis associated with Southeast Asian ovalocytosis. Kidney Int. 1999; 56:1674–1682. PMID: 10571775.

25. Kittanakom S, Cordat E, Akkarapatumwong V, Yenchitsomanus PT, Reithmeier RA. Trafficking defects of a novel autosomal recessive distal renal tubular acidosis mutant (S773P) of the human kidney anion exchanger (kAE1). J Biol Chem. 2004; 279:40960–40971. PMID: 15252044.

26. Quilty JA, Li J, Reithmeier RA. Impaired trafficking of distal renal tubular acidosis mutants of the human kidney anion exchanger kAE1. Am J Physiol Renal Physiol. 2002; 282:F810–F820. PMID: 11934690.

27. Cordat E, Kittanakom S, Yenchitsomanus PT, et al. Dominant and recessive distal renal tubular acidosis mutations of kidney anion exchanger 1 induce distinct trafficking defects in MDCK cells. Traffic. 2006; 7:117–128. PMID: 16420521.

28. Kittanakom S, Cordat E, Reithmeier RA. Dominant-negative effect of Southeast Asian ovalocytosis anion exchanger 1 in compound heterozygous distal renal tubular acidosis. Biochem J. 2008; 410:271–281. PMID: 17941824.

29. Rungroj N, Devonald MA, Cuthbert AW, et al. A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells. J Biol Chem. 2004; 279:13833–13838. PMID: 14734552.

30. Devonald MA, Smith AN, Poon JP, Ihrke G, Karet FE. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Nat Genet. 2003; 33:125–127. PMID: 12539048.