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1st
appeared 6 May 1999
Studies of A Gene for A Rare Form of Rickets
Shed Light on Vitamin D Deficiencies
Two years after they cloned the gene for a vital kidney enzyme, vitamin D-1-alpha
hydroxylase, UCSF researchers 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, professor of pediatrics and chief of pediatric nephrology at UCSF,
presented these findings in a 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 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."
Links:
UCSF Plays Major Role at
Pediatrics Meetings
Researchers Clone Gene Vital
for Vitamin D Metabolism
Source: Janet Basu, News Services |
