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

Anthony Portale, MD, professor of pediatrics and chief ofpediatric nephrology at UCSF, presented these findings in aninvited symposium at the Pediatric Academic Societies'annual meeting in San Francisco on Sunday, May 2. Portaleand workers in the laboratory of pediatric endocrinologistWalter L. Miller, MD, collaborated in cloning the gene forthe enzyme in 1997.

The 1-alpha hydroxylase enzyme works in the kidney toperform one of the final steps in a long process thatconverts vitamin D -- the vitamin that comes in a morningglass of milk or is made when the skin is exposed tosunlight -- into a hormone called calcitrol. The main workfor calcitrol as a hormone is to regulate the absorption ofcalcium from the intestine into the blood and the depositionof calcium into bone. Without it, adult bones become brittleand children's bones do not grow. The calcitrol-calciumcombination also is necessary to aid nerve growth and musclefunction.

"Work with the gene has provided more evidence for what wealready suspected -- that production of the active form ofvitamin D hormone by the kidneys is essential for normalbone health and bone growth in children," Portale said. Thisis a particular concern for his patients; he leads thepediatric kidney dialysis and nephrology practice for LucilePackard Children's Hospital at UCSF. People with kidneyfailure do not have a genetic deficiency in vitamin Dmetabolism, but without normal kidney function they lose theability to make vitamin D in its active form.

Since cloning the 1-alpha hydroxylase gene, Portale and hiscolleagues have identified mutations in 19 patients.Children with these rare mutations cannot convert vitamin Dto calcitrol, and so suffer from rickets. "We now canidentify carriers of the gene in families," Portale said."We also can help make a diagnosis in a child who might have1-alpha hydroxylase deficiency, and clarify the prognosis.Once the genetic tests have been done, the physician candecide whether the child needs short-term nutritionaltherapy for rickets, or a lifetime of treatment withreplacement amounts of the active hormone."

Replacing the missing vitamin D hormone is a solution formost children, Portale said: "The rickets begin to heal, thebone deformities improve, the blood chemical values returnto normal. And the child begins to grow more normally."

Of the 19 people that Miller and Portale have studied with1-alpha hydroxylase rickets, 14 have different mutations ofthe gene controlling production of the vitamin D enzyme. Ina related disease, X-linked hypophosphatemic rickets, the1-alpha hydroxylase gene is normal but factors regulating itare abnormal; this problem is under active study by thePortale and Miller groups. Regulation of the enzyme also canbe abnormal in aging, and may contribute to osteoporosis.

"The long term goal of this work is to understand how thevitamin D enzyme is regulated, how it does its work, and howthese processes are abnormal in certain diseases," Portalesaid. "The most dramatic effects come with complete loss ofthe enzyme's function. But in other cases the function ispartial or abnormal, and that causes diseases that may needdifferent approaches to treatment."

Principal investigators Anthony Portale, MD, and Walter L.Miller, MD, are professors of pediatrics at the Universityof California, San Francisco. Much of the cloning work wasdone by Glenn K Fu, PhD, and the genetic analysis work byJonathan T. Wang, PhD, who are fellows in pediatricendocrinology at UCSF. This research is supported by grantsfrom the National Institutes of Health, the March of DimesBirth Defects Foundation, and the Carmel David Trust.

For a report on the 1997 cloning of vitamin D-1-alphahydroxylase, see http://www.ucsf.edu/daybreak/1997/11/1103_met.htr