Apr. 22, 2002 St. Louis, April 18, 2002 — Researchers have uncovered new information about a gene that when mutated prevents the kidneys from filtering properly. The mutation causes a rare disorder known as nail-patella syndrome, which frequently involves kidney abnormalities.
“This gene, known as Lmx1b, regulates production of other proteins that are required for normal kidney function,” says Jeffrey H. Miner, Ph.D., assistant professor of medicine and of cell biology and physiology at the Washington University School of Medicine in St. Louis and lead author of the paper. “Our findings should improve the understanding of nail-patella syndrome and of kidney function and failure.” The findings appear in the April 15 issue of The Journal of Clinical Investigation.
The study, done using mice, found that mutations in the Lmx1b gene cause a reduction in levels of two proteins known as CD2AP and podocin. Both proteins are necessary for kidney cells known as podocytes to mature and function properly.
Podocytes form the filtering mechanism within the kidneys. Mature podocytes have long branching strands that entwine capillaries within the kidneys. Normally, these strands work with strands from neighboring cells to form a molecular meshwork, or slit diaphragms, that probably work like sieves or strainers.
“Slit diaphragms allow water and dissolved toxins like urea to leave the bloodstream while holding back protein molecules the body needs in the blood,” says Miner. Much of the water is reabsorbed by the kidney and the rest, along with the urea, is collected and expelled as urine.
The study showed that podocytes from mice with the Lmx1b mutation have the appearance of immature podocytes and lack the ultrafine filter. “This helps explain why people with Lmx1b mutations and nail-patella syndrome can have kidney problems,” says Miner.
Exactly how mutations in Lxm1b cause nail-patella syndrome remains poorly understood. The syndrome, which has an incidence of 4.5 cases per million people, typically causes somewhat misshaped elbows, under-formed kneecaps (patella), and pitted, wrinkled or misshaped fingernails. These abnormalities occur to different degrees in people with the syndrome.
About 30 percent of people with nail-patella syndrome also have kidney problems, which can range from small amounts of blood or protein in the urine to progressive kidney failure.
Miner JH, Morello R, Andrews KL, Li C, Antignac C, Shaw AS, Lee B. Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation. The Journal of Clinical Investigation. 109(8), 1065-1072, April 15, 2002.
The research was funded by grants from the National Institutes of Health, the Arthritis Foundation and Telethon-Italy.
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