Review Article J Mol Genet Med (December 2005), 1(2), 49-62 doi: jmgm Published online: 16 November 2005 Full Text: (html | pdf ~520kb | refs) Molecular mechanisms of autosomal dominant and recessive distal renal tubular acidosis caused by SLC4A1 (AE1) mutations Pa-thai Yenchitsomanus †‡§*, Saranya Kittanakom ¥, Nanyawan Rungroj §, Emmanuelle Cordat ¥, Reinhart A F Reithmeier ¥ † Division of Medical Molecular Biology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand *Correspondence to: Pa-thai Yenchitsomanus, Email: grpye@mahidol.ac.th, Tel: +662 4197000 ext 6666 70, Fax: +662 4184793 Received: 14 July 2005, Revised: 06 September 2005, Accepted: 13 September 2005 © Copyright The Authors Reviewers of this article included Professor Oliver Wrong (London, United Kingdom) ----------------------------------------------------------------------------------------------------------------- ABSTRACT Mutations of SLC4A1 (AE1) encoding the kidney anion (Cl -/HCO 3 -) 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. KEYWORDS: Distal renal tubular acidosis, kidney anion exchanger, protein trafficking, dominant negative effect, dominant positive effect ----------------------------------------------------------------------------------------------------------------- Privacy | Disclaimer |