Public Release: 

Studies Of A Gene For A Rare Form Of Rickets Shed Light On Vitamin D Deficiencies

University of California - San Francisco

Two years after they cloned the gene for a vital kidney enzyme, vitamin D-1-alpha hydroxylase, researchers at the University of California San Francisco are beginning to understand how the enzyme works. They are learning how it is regulated normally and how it acts abnormally in both a rare inherited form of rickets and in common forms of vitamin D deficiency, for example bone growth problems caused by chronic kidney failure or by aging.

Anthony Portale, M.D., professor of pediatrics and chief of pediatric nephrology at UCSF, presented these findings in an invited symposium at the Pediatric Academic Societies' annual meeting in San Francisco on Sunday, May 2. Portale and workers in the laboratory of pediatric endocrinologist Walter L. Miller, M.D., collaborated in cloning the gene for the enzyme in 1997.

The 1-alpha hydroxylase enzyme works in the kidney to perform one of the final steps in a long process that converts vitamin D -- the vitamin that comes in a morning glass of milk or is made when the skin is exposed to sunlight -- into a hormone called calcitrol. The main work for calcitrol as a hormone is to regulate the absorption of calcium from the intestine into the blood and the deposition of calcium into bone. Without it, adult bones become brittle and children's bones do not grow. The calcitrol-calcium combination also is necessary to aid nerve growth and muscle function.

"Work with the gene has provided more evidence for what we already suspected -- that production of the active form of vitamin D hormone by the kidneys is essential for normal bone health and bone growth in children," Portale said. This is a particular concern for his patients; he leads the pediatric kidney dialysis and nephrology practice for Lucile Packard Children's Hospital at UCSF. People with kidney failure do not have a genetic deficiency in vitamin D metabolism, but without normal kidney function they lose the ability to make vitamin D in its active form.

Since cloning the 1-alpha hydroxylase gene, Portale and his colleagues have identified mutations in 19 patients. Children with these rare mutations cannot convert vitamin D to calcitrol, and so suffer from rickets. "We now can identify carriers of the gene in families," Portale said. "We also can help make a diagnosis in a child who might have 1-alpha hydroxylase deficiency, and clarify the prognosis. Once the genetic tests have been done, the physician can decide whether the child needs short-term nutritional therapy for rickets, or a lifetime of treatment with replacement amounts of the active hormone."

Replacing the missing vitamin D hormone is a solution for most children, Portale said: "The rickets begin to heal, the bone deformities improve, the blood chemical values return to normal. And the child begins to grow more normally." Of the 19 people that Miller and Portale have studied with 1-alpha hydroxylase rickets, 14 have different mutations of the gene controlling production of the vitamin D enzyme. In a related disease, X-linked hypophosphatemic rickets, the 1-alpha hydroxylase gene is normal but factors regulating it are abnormal; this problem is under active study by the Portale and Miller groups. Regulation of the enzyme also can be abnormal in aging, and may contribute to osteoporosis.

"The long term goal of this work is to understand how the vitamin D enzyme is regulated, how it does its work, and how these processes are abnormal in certain diseases," Portale said. "The most dramatic effects come with complete loss of the enzyme's function. But in other cases the function is partial or abnormal, and that causes diseases that may need different approaches to treatment."

Principal investigators Anthony Portale, M.D., and Walter L. Miller, M.D., are professors of pediatrics at the University of California, San Francisco. Much of the cloning work was done by Glenn K Fu, Ph.D., and the genetic analysis work by Jonathan T. Wang, Ph.D., who are fellows in pediatric endocrinology at UCSF. This research is supported by grants from the National Institutes of Health, the March of Dimes Birth Defects Foundation, and the Carmel David Trust.


For a report on the 1997 cloning of vitamin D-1-alpha hydroxylase, see

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