Last fall, researchers at UCSF announced that they had identified an elusive gene critical for vitamin D metabolism. Now they have identified mutations in that gene, paving the way for genetic diagnosis of a hereditary form of childhood rickets.

Further analysis of the gene, say the researchers, could lead to an understanding of other vitamin D deficiency disorders as well.

The finding, presented at the Pediatric Academic Society's annual meeting in New Orleans on Saturday, May 2, will even allow for prenatal diagnosis of the metabolic disorder, known as vitamin D-dependent rickets. It will also allow for genetic testing of adults to determine if they carry a latent form of the genetic mutation that could be passed on to their offspring.

"Identifying the genetic mutations that cause hereditary vitamin D-dependent rickets is likely to increase the number of diagnoses made of the condition, which will allow for earlier treatment," said Walter Miller, UCSF professor of pediatrics and senior author of the study.

"And being able to genetically diagnose adults as carriers of the mutated gene," he said, "will enable us to alert parents to the possibility that their future offspring may carry the disease. This way the children can be evaluated for the disorder and, if necessary, begin treatment early in life."

Children with hereditary vitamin D-dependent rickets cannot metabolize vitamin D to its active hormonal form and, as a result, have difficulty growing healthy bone. They develop poorly, have abnormal teeth and develop rickets, or deformed bones. The condition is corrected by treatment with a synthetic form of the active vitamin D hormone.

The researchers carried out their study by examining samples of DNA collected from 20 patients in 18 different families from around the world. They identified nine mutations in the gene, known as P4501 alpha, and determined that these mutations give rise to truncated enzymes that are unable to carry out their catalytic activity.

Six samples of the DNA were from French Canadians, among whom the disease is common. The UCSF researchers found that all of these individuals carried the same mutation in the gene, and they have devised a rapid test for the mutation that can be used for genetic diagnosis. Other patients examined in the UCSF study included Poles, Filipinos, African-Americans and Caucasians, one Chinese and one Haitian.

The researchers are now examining the various P4501 alpha mutations in cultured cells, with the intent of trying to identify correlations between specific forms of the mutation and the resulting enzyme activity. Ultimately, they hope to link specific errors in the enzyme to specific clinical manifestations in individual patients.

"People have different degrees of severity and times of onset of the condition," said Miller. "It may be that we will be able to find a correlation between the specific mutations and clinical manifestations of the disease."

by Jennifer O'Brien

1st appeared 5/4/98

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