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EDITORIAL FOCUS

Collecting evidence: the case of collectrin (Tmem27) and amino acid transport

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland

WITH COMPLETION of the Human Genome Project in 2001 (4) came the capacity to identify the sequence, but not necessarily the function, of any human gene. This limitation remains an issue for students of amino acid metabolism and transport, whose discipline originated a century ago with Sir Archibald Garrod's description of alkaptonuria (2), an autosomal recessive disorder of tyrosine degradation due to the deficiency of homogentisic acid dioxygenase (6). The next major advance in the field of amino acid metabolism occurred in the 1950s and involved the ability to measure amino acids in urine and plasma using ion exchange chromatography. Over the subsequent decades, a panoply of human metabolic disorders involving amino acids was described on clinical and molecular grounds, and therapies were advanced for many of these (7).

Despite vast increases in our knowledge of amino acid pathways, the genetic basis of amino acid transport has remained poorly elucidated. Causative genes and distinct mutations have been identified only for lysinuric protein intolerance, cystinuria (a dibasic aminoaciduria), and Hartnup disorder (a neutral aminoaciduria) (8). Iminoglycinuria, dicarboxylic aciduria, and other forms of Hartnup disorder still await identification of the responsible genes and of the functional bases of the physiological defects involved. Finally, the reasons for generalized aminoaciduria in isolated glucosuria and renal Fanconi syndrome continue to beg for explanations. In short, the field needs to know what regulates amino acid reabsorption.

A significant step toward answering this query is provided by Malakauskas et al. (5) in this issue of the American Journal of Physiology-Renal Physiology. This group describes a previously unknown function of Tmem27, also known as collectrin for its expression in the renal collecting duct (9). Le's group created a knockout mouse and described abnormalities in amino acid transport responsible for findings of an osmotic diuresis. They provide evidence for decreased amounts of the amino acid transporters Slc6a19 (B⁰AT1), Slc7a9 (B^0,+AT), and Slc3a1 (rBAT) in the luminal plasma membrane of the knockout mice and suggest that collectrin mediates amino acid absorption in the proximal tubule.

Collectrin, however, like the classic Hartnup disorder gene SLC6A19 (3), also has extrarenal expression. Both of these genes are expressed in the liver, and collectrin's role as a target of the transcription factor HNF-1 provides a potential regulatory link between amino acid metabolism in the liver and amino acid transport in the kidney. Collectrin's recently described function in controlling insulin exocytosis by modulating N-ethylmaleimide-sensitive fusion attachment receptor complex formation may provide a clue to its mechanism of action in proximal tubular cells (1).

The findings of Malakauskas et al. (5) raise several questions, which reflect the work's huge potential for insight into renal amino acid transport. Are all amino acids affected by collectrin deficiency? Which other transporters are involved? How does collectrin cause an increase in the presence of amino acid transporters within the plasma membranes of proximal tubule cells? Does binding to collectrin confer stabilization and reduce degradation? Can collectrin, an integral membrane protein, create a net flux of amino acid transporters by retaining them in the plasma membrane? Are N-ethylmaleimide-sensitive fusion attachment receptor proteins involved in collectrin's renal functions? Do amino acid transporters traffic to the plasma membrane via vesicles in a manner resembling the movement of insulin in pancreatic cells? Finally, will the phenotype in humans resemble the picture in mice?

The answers to these questions will provide an understanding of the mechanism and regulation of amino acid transport in renal tubules; collectrin is likely to play a significant role. Further investigations will also offer insight into the pathogenesis of human disorders involving amino acidurias that are either isolated or associated with systemic disease. The time is ripe to begin acquiring critical experimental evidence. Let the collecting begin!

	FOOTNOTES

 

Address for reprint requests and other correspondence: R. Kleta, SHBG, MGB, National Human Genome Research Institute, National Institutes of Health, Bldg. 10, Rm. 10C103, 10 Center Dr., Bethesda, MD 20892-1851 (e-mail:kletar{at}mail.nih.gov)

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This Article Full Text (PDF) All Versions of this Article: 292/2/F531    most recent 00409.2006v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Kleta, R. Articles by Gahl, W. A. Search for Related Content PubMed PubMed Citation Articles by Kleta, R. Articles by Gahl, W. A.