Update of Cystinuria Research

By John Endsley, M.D.
Vanderbilt University Medical Center
Nashville TN

Medical research can be divided into two categories: “basic science” and “clinical” research. The basic science research asks questions about how organisms (like people) and disease processes work, without a specific plan for how to apply that knowledge to treat disease. Clinical research asks questions about how to develop better treatments for patients, sometimes without knowing all the details of why a treatment works. The two approaches feed off of each other, because understanding how a disease works usually leads to better ideas about how to treat it. In the case of cystinuria research, up until fairly recently there has been little new information from basic science research, and slow progress in clinical research. In the past few years, however, a number of breakthroughs have occurred in basic science research in cystinuria, and I will simplify and summarize the most important ones in the remainder of this article. To those with some background in molecular biology this may seem oversimplified.

Cystinuria is an inherited disease, usually transmitted in what is termed “autosomal recessive” fashion. The disease is manifested by a decreased ability of the kidney to reabsorb certain amino acids from the urine as it is being formed. One of the amino acids, cystine, does not dissolve well in urine, and when too much of it is present it may lead to formation of kidney stones. One of the main aims of basic science research in cystinuria has been to identify the gene or genes which causes the disease.

One of the genes has now been identified. In 1992, two groups1,2 independently isolated (cloned) genes that caused increased transport of cystine when it was expressed in a special type of frog cell (Expression means that the DNA of the gene was injected into the cell and “translated” by the cell to make a protein. The protein in this case then was inserted into the cell membrane and caused cystine to be taken up by the cell.). One gene was isolated in rat (this gene was called D2), the other in rabbit (this gene was called rBAT). When the DNA sequences of the genes were compared, they were extremely similar to each other. This lead to speculation that a similar gene in humans could be one of the genes damaged in patients with cystinuria, and in 1993, a human gene with DNA sequences very similar to the rat and rabbit genes was isolated3. The location of this gene was found to be on chromosome 24. The human gene was designated SLC3A1. The protein produced from this gene is usually referred to as rBAT

The next breakthrough came in 1994, when samples from some patients with cystinuria were found to have abnormalities (or “mutations”) in the DNA sequences of the SLC3A1 gene5. When proteins were produced using these damaged versions of the gene, they were found to have a decreased ability to transport cystine across a cell membrane, which is what one would expect of a gene causing cystinuria. Since then, a number of other investigators have found other abnormalities in this gene in cystinuric patients.

Up until recently, most of the mutations were found by a very labor intensive process which required manipulating the cells obtained from cystinuric patients to make them produce a copy of the gene in a version called “mRNA”. This need to process each patient’s sample shortly after obtaining it and over a period of weeks had limited the ability of investigators to screen many patients for abnormalities. Recently, however, both our group at Vanderbilt and Dr. Pras6 in Israel have independently decoded the “genomic structure (the sequence of “introns” and “exons”) of the SLC3A1 gene. This should allow more efficient screening of patient samples, since it eliminates the need to manipulate the cells to produce mRNA. Several new mutations have been identified using this technique.

It is currently felt that there are probably other genes involved in causing cystinuria in some patients. Future efforts in basic science research in cystinuria will probably focus on continued exploration of the structure and function of SLC3A1 and the rBAT protein as well as finding other genes that can cause cystinuria. Ultimately, the hope is that we can design ways to correct the defect by inserting a corrected copy of the gene into the kidney cells of patients and allow them to begin taking up cystine to prevent further kidney stones. Those of us involved in research appreciate those with the disease who have given samples for these studies, and we also understand the frustration you must feel knowing that this progress in basic science may take years to spill over into clinical trials of new therapies. Thank you for your help, and hang in there.


1. Wells RG, Heidiger MA: Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proceedings of the National Academy of Sciences of the United States of America 89:5596-5600, 1992

2. Bertran J, et al: Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic and neutral amino acids. Proceedings of the National Academy of Sciences of the United States of America 89:5601-5605, 1992

3. Bertran J, et al: Expression cloning of a human renal cDNA that induces high affinity transport of L-cystine shared with dibasic amino acids in Xenopur oocytes. Journal of Biological Chemistry 268:14842-14849, 1993

4. Pras E, et al: Localization of a gene causing cystinuria to chromosome 2p. Nature Genetics 6:415-419, 1994

5. Calonge MJ, et al: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. . Nature Genetics 6:420-425, 1994

6. Pras E, et al: Genomic organization of SLC3A1, a transporter gene mutated in cystinuria. Genomics 36:163-167, 1996

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