Footnotes Competing Interests: The authors have declared that no competing interests exist. Funding: The authors were funded by the Institute for Pathology, University Hospital of Basel, Research pool account. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
autosomal recessive proximal http://www.selleckchem.com/products/azd9291.html renal tubular acidosis is characterized by severe proximal tubule bicarbonate wasting, hyperchloremic metabolic acidosis, and hypokalemia (11, 20, 21, 25�C27, 39, 50, 54). In addition to a renal phenotype, these patients have extrarenal manifestations involving the eye that includes glaucoma, cataracts, and band keratopathy. Mental retardation, short stature, teeth abnormalities, an elevated serum amylase, thyroid abnormalities, and basal ganglia calcification have also been reported (11, 20, 21, 25�C27, 39, 50, 54).

All patients characterized thus far have mutations in the electrogenic sodium bicarbonate cotransporter NBCe1 encoded by the SLC4A4 gene (1). Renal bicarbonate wasting results from the loss of normal NBCe1-A-mediated basolateral proximal tubule bicarbonate absorption. The extrarenal manifestations are due to the finding that NBCe1 also plays an important role in bicarbonate transport/pH regulation in various organs (46). Currently, 10 unique mutations throughout the cotransporter have been reported. The location of these mutations is depicted in Fig. 1 based on one of the putative current topological models of NBCe1.1 Fig. 1. Putative location of mutations in NBCe1-A in patients with autosomal recessive proximal renal tubular acidosis.

Of the known mutations in NBCe1, three mutations that cause premature truncation of the cotransporter have been described (21, 26, 27). In the NBCe1-A-Q29X nonsense mutation causing proximal renal tubular acidosis, a wild-type CAG codon encoding glutamine has been replaced by a UAG stop codon, resulting in premature truncation of the cotransporter (26). NBCe1 has three functional variants, NBCe1-A, NBCe1-B, and NBCe1-C; however, only NBCe1-A possesses a unique NH2 terminus containing Gln-29 and is therefore the only variant prematurely truncated in these patients as a result of the Q29X mutation.

Currently, hundreds of nonsense mutations causing human disease are known, including those causing Alport’s syndrome (28), diabetes insipidus (48), cystic fibrosis (63), Duchenne muscular dystrophy (23, 60), ataxia-telangiectasia (64), Hurler syndrome (32), hemophilia A (66), hemophilia B (34), and Cilengitide Tay-Sachs (2). Unfortunately, for many of those diseases there is presently no effective treatment. Although gene therapy seems like a potential possible solution for these genetic disorders, there are still many critical difficulties to be solved before this technique can be used in humans.