Gene Defect Causes Abnormal Calcium Metabolism

This work, published in the April 2002 issue of the Journal of Clinical Endocrinology and Metabolism, shows that a mutation marked by six base substitutions in an adenylate cyclase gene causes absorptive hypercalciuria (AH), a condition that causes the intestine to overabsorb calcium and is the basis for about 45% of all kidney stones.

A research team from the University of Texas Southwestern Medical Center (Dallas, USA) searched for genetic similarities in families with AH. They found a gene that was similar to a recently described rat adenylate cyclase gene (with function unrelated to calcium metabolism) and subsequently identified the six base substitutions in this gene that occurred far more frequently in AH patients. The presence of at least one of the six base substitutions translates into a 2.2- to 3.5-fold increase in the risk of having AH. The presence of more than one of the base substitutions increases risk even more; people who carry any five of the base substitutions are 11.5 times as likely to have AH as those with the normal gene structure.

"It represents the molecular elucidation of a clinical syndrome,” says Dr. Charles Y. C. Pak, senior author of the study. "It is the result of 30 years of work on a clinical syndrome and its molecular explanation.”

As part of the study, patients' bone mineral density in the lower spine was measured, and the presence of one or more of the six base changes was associated with lower vertebral bone density in the lumbar region. The researchers say the study provides a definite marker for kidney-stone risk, but it might also lead to early-stage identification and treatment for bone loss and osteoporosis.

"I think many idiopathic osteoporosis patients carry this genetic defect,” Dr. Pak said. "And if a woman is postmenopausal and has the genetic defect, she's even more likely to get bone loss.”




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University of Texas Southwestern Medical Center