Pittsburgh researchers discover genetic link between two juvenile onset renal diseases

December 09, 2002

PITTSBURGH, Dec. 5 - Geneticists from the University of Pittsburgh have identified mutations in a gene that are responsible for two heritable kidney diseases. The discovery of four novel gene mutations in the uromodulin (UMOD) gene which are responsible for medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN) proves that these two diseases are actually the same condition, according to a study from the team of researchers led by the University of Pittsburgh School of Dental Medicine. These findings, published in the December issue of the Journal of Medical Genetics, will allow physicians to more effectively test patients for this condition.

The geneticists from the University of Pittsburgh studied DNA from members of several large families with multiple members having progressive kidney failure and gout. The group, led by Thomas Hart, D.D.S., Ph.D., associate professor of oral pathology and medicine at the University of Pittsburgh School of Dental Medicine, was able to identify a small genetic change in the UMOD gene in all affected family members. The product of this gene, a protein called uromodulin is the most common protein in normal urine. Despite its being so common, the precise role of uromodulin is unknown. This study presents the first discovery of genetic defects in this gene, making the role of uromodulin more apparent. The identification of mutations in the UMOD gene will allow testing of clinically unaffected family members to identify those with the gene defect, permitting treatment intervention before significant pathology has occurred.

"If we are able to test children and siblings of individuals already diagnosed with this condition, we can diagnose and treat the disease early, possibly preventing the progression of kidney disease in these patients," said Dr. Thomas Hart.

Prior to the findings in this study, it was known that both MCKD2 and FJHN were heritable renal diseases that share common symptoms such as progressive renal failure, hyperuricemia (an excess of uric acid in the blood), gout and polyurea (the passage of large amounts of urine at one time). Before this discovery, the basic defect in these conditions was not known. Primary clinical features of the two diseases varied in presence and severity that made diagnosing patients complicated.

Working with Dr. Anthony Bleyer of the Wake Forest University School of Medicine, the researchers obtained samples from four families, three with FJHN and one with MCKD2. The Pittsburgh group then conducted genetic linkage and mutational analysis tests on the samples and determined that four mutations in the UMOD gene were responsible for both diseases, making them the same disease. This discovery will allow physicians to develop a genetic test to diagnose this condition, which previously was very difficult to diagnose.

"Understanding the role of uromodulin in normal kidney function as well as in disease may provide valuable insights for the diagnosis and treatment of renal disease and gout. Currently there are approximately 350,000 people on dialysis, and 1 million suffering from kidney failure. An estimated 25 percent have no diagnosed cause of renal disease. This new genetic test will allow us to give some of these patients a diagnosis and determine the frequency of the disease in the population," said Dr. Hart.
Other members of the research team from the University of Pittsburgh include Michael Gorry, Suzanne Hart, Ph.D., Brian Shirts, Linda Xu and Michael Barmada, Ph.D. The study was funded in part by a United States Public Health Service research grant from the National Institute of Diabetes and Digestive and Kidney Diseases.

Additional Contact:
Frank Raczkiewicz
PHONE: (412) 647-3555
FAX: (412) 624-3184

University of Pittsburgh Medical Center

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