The human chloride/bicarbonate AE1 (anion exchanger) is a dimeric glycoprotein expressed in the red blood cell membrane, and expressed as an N-terminal (Δ1–65) truncated form, kAE1 (kidney AE1), in the basolateral membrane of α-intercalated cells in the distal nephron. Mutations in AE1 can cause SAO (Southeast Asian ovalocytosis) or dRTA (distal renal tubular acidosis), an inherited kidney disease resulting in impaired acid secretion. The dominant SAO mutation (Δ400–408) that results in an inactive transporter and altered eythrocyte shape occurs in many dRTA families, but does not itself result in dRTA. Compound heterozygotes of four dRTA mutations (R602H, G701D, ΔV850 and A858D) with SAO exhibit dRTA and abnormal red blood cell properties. Co-expression of kAE1 and kAE1 SAO with the dRTA mutants was studied in polarized epithelial MDCK (Madin–Darby canine kidney) cells. Like SAO, the G701D and ΔV850 mutants were predominantly retained intracellularly, whereas the R602H and A858D mutants could traffic to the basolateral membrane. When co-expressed in transfected cells, kAE1 WT (wild-type) and kAE1 SAO could interact with the dRTA mutants. MDCK cells co-expressing kAE1 SAO with kAE1 WT, kAE1 R602H or kAE1 A858D showed a decrease in cell-surface expression of the co-expressed proteins. When co-expressed, kAE1 WT co-localized with the kAE1 R602H, kAE1 G701D, kAE1 ΔV850 and kAE1 A858D mutants at the basolateral membrane, whereas kAE1 SAO co-localized with kAE1 WT, kAE1 R602H, kAE1 G701D, kAE1 ΔV850 and kAE1 A858D in MDCK cells. The decrease in cell-surface expression of the dRTA mutants as a result of the interaction with kAE1 SAO would account for the impaired expression of functional kAE1 at the basolateral membrane of α-intercalated cells, resulting in dRTA in compound heterozygous patients.
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March 2008
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Research Article|
February 12 2008
Dominant-negative effect of Southeast Asian ovalocytosis anion exchanger 1 in compound heterozygous distal renal tubular acidosis
Saranya Kittanakom;
Saranya Kittanakom
1Departments of Biochemistry and Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
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Emmanuelle Cordat;
Emmanuelle Cordat
1Departments of Biochemistry and Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
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Reinhart A. F. Reithmeier
Reinhart A. F. Reithmeier
1
1Departments of Biochemistry and Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
1To whom correspondence should be addressed (email r.reithmeier@utoronto.ca).
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Publisher: Portland Press Ltd
Received:
May 08 2007
Revision Received:
October 15 2007
Accepted:
October 17 2007
Accepted Manuscript online:
October 17 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 410 (2): 271–281.
Article history
Received:
May 08 2007
Revision Received:
October 15 2007
Accepted:
October 17 2007
Accepted Manuscript online:
October 17 2007
Citation
Saranya Kittanakom, Emmanuelle Cordat, Reinhart A. F. Reithmeier; Dominant-negative effect of Southeast Asian ovalocytosis anion exchanger 1 in compound heterozygous distal renal tubular acidosis. Biochem J 1 March 2008; 410 (2): 271–281. doi: https://doi.org/10.1042/BJ20070615
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