alexa Molecular mechanisms of autosomal dominant and recessive distal renal tubular acidosis caused by SLC4A1 (AE1) mutations | OMICS International | Abstract
ISSN: 1747-0862

Journal of Molecular and Genetic Medicine
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Review Article

Molecular mechanisms of autosomal dominant and recessive distal renal tubular acidosis caused by SLC4A1 (AE1) mutations

Pa-thai Yenchitsomanus1,2,3,*, Saranya Kittanakom4, Nanyawan Rungroj3, Emmanuelle Cordat4, Reinhart A F Reithmeier4

1Division of Medical Molecular Biology and Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

2BIOTEC-Medical Biotechnology Unit, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

3Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

4Departments of Biochemistry and Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

*Corresponding Author:
Pa-thai Yenchitsomanus
Tel: +662 4197000 ext 6666-70
Fax: +662 4184793
Email: [email protected]

Received 14 July 2005; Revised 06 September 2005; Accepted 13 September 2005; Available online 16 November 2005; Published 30 December 2005

© Copyright: Pa-thai Yenchitsomanus et al

Abstract

Mutations of SLC4A1 (AE1) encoding the kidney anion (Cl-/HCO3 -) exchanger 1 (kAE1 or band 3) can result in either autosomal dominant (AD) or autosomal recessive (AR) distal renal tubular acidosis (dRTA). The molecular mechanisms associated with SLC4A1 mutations resulting in these different modes of inheritance are now being unveiled using transfected cell systems. The dominant mutants kAE1 R589H, R901X and S613F, which have normal or insignificant changes in anion transport function, exhibit intracellular retention with endoplasmic reticulum (ER) localization in cultured non-polarized and polarized cells, while the dominant mutants kAE1 R901X and G609R are mis-targeted to apical membrane in addition to the basolateral membrane in cultured polarized cells. A dominant-negative effect is likely responsible for the dominant disease because heterodimers of kAE1 mutants and the wild-type protein are intracellularly retained. The recessive mutants kAE1 G701D and S773P however exhibit distinct trafficking defects. The kAE1 G701D mutant is retained in the Golgi apparatus, while the mis-folded kAE1 S773P, which is impaired in ER exit and is degraded by proteosome, can only partially be delivered to the basolateral membrane of the polarized cells. In contrast to the dominant mutant kAE1, heterodimers of the recessive mutant kAE1 and wild-type kAE1 are able to traffic to the plasma membrane. The wild-type kAE1 thus exhibits a ‘dominant-positive effect’ relative to the recessive mutant kAE1 because it can rescue the mutant proteins from intracellular retention to be expressed at the cell surface. Consequently, homozygous or compound heterozygous recessive mutations are required for presentation of the disease phenotype. Future work using animal models of dRTA will provide additional insight into the pathophysiology of this disease.

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