Research Updates in Kidney and Urologic Health

Researchers Use Genomic Tools to Unlock ARPKD Gene

Two Teams of NIDDK-Supported Scientists Identify Human PKHD1

Working independently, teams of researchers at the Mayo Clinic and Johns Hopkins University have isolated the gene responsible for autosomal recessive polycystic kidney disease (ARPKD) and traced its mode of expression. ARPKD is sometimes referred to as "infantile PKD" because the kidney and liver damage it causes is seen early in life, even before birth, and often results in infant death. The gene, given the name PKHD1, encodes a large protein that is expressed in cells of the biliary tract and collecting ducts of the kidney. Mutations in PKHD1 may result in multiple fluid-filled cysts on the kidney and fibrosis in the liver.

The Mayo Clinic team, led by Peter Harris, Ph.D., analyzed genetic samples from a rat with recessive PKD and found sequences that compared with human ARPKD genes. Identifying the orthologous genes (derived from a common ancestor species) allowed the team to identify the human PKHD1 gene and predict that it encodes a large unique protein. This information will be essential for ultimately understanding the protein's function and its role in causing ARPKD. Dr. Harris and his colleagues published their findings in the March 2002 issue of Nature Genetics.

Gregory Germino, M.D., of Johns Hopkins is the principal investigator for a program that has been investigating the molecular genetics of ARPKD. He has also worked with other investigators in recruiting families with ARPKD to create a database of genetic samples for analysis. An article by Dr. Germino and colleagues in the May 2002 issue of the American Journal of Human Genetics describes the predicted product of human PKHD1 as a novel, large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix repeats. These structural features are characteristic of proteins that are involved in regulating cell proliferation and cellular adhesion.

Scientists hope that this new knowledge will lead to advances in the diagnosis and treatment of ARPKD. Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute at the National Institutes of Health, said that with the identification of the responsible gene and the characterization of a rat model of the disease, "Rapid progress in understanding ARPKD can be anticipated. The ARPKD gene identification is a marvelous piece of scientific sleuthing."

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) funds several laboratories performing genetic as well as clinical research into many forms of kidney disease. Dr. Harris received a 5-year grant to study transgenic and knockout models of autosomal dominant polycystic kidney disease. Dr. Germino has NIDDK support for programs in PKD protein interactions and the molecular genetics of human ARPKD.

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