Missouri genetic disorder’s roots untangled by international team

An international team of researchers has partially untangled the genetic details of a mysterious disorder that formerly caused seizures and death in infant boys within a month of birth.

The researchers discovered a rare change in the DNA of two eastern Missouri families with a history of a condition called X-linked recessive idiopathic hypoparathyroidism (XLHPT): a portion of the X chromosome, a human sex chromosome, has been removed and replaced by a copy of a much larger section of genetic material from chromosome 2. Alterations of such large regions of genetic code that stably pass from one generation to the next are generally rare and have never before been observed in the human X chromosome.

The study was led by scientists at Oxford University in England and included researchers from Washington University School of Medicine and Shriners Hospital for Children in St. Louis.

In the long term, the disorder’s links to blood calcium levels and parathyroid hormone secretion may someday help scientists seeking to develop new treatments for osteoporosis. For now, though, the findings almost bring to a close a decades-long investigation into the disorder that has plagued two Missouri families for generations.

“So far, XLHPT has only been observed in these two eastern Missouri families and it only affects males–the females are carriers,” says Michael Whyte, M.D., professor of medicine, pediatrics and of genetics at Washington University School of Medicine. “Seizures and death within a month of birth is a dramatic set of symptoms, so if this problem had ever developed anywhere else in the world, it seems likely that it would have been reported.”

The findings appear in the October issue of The Journal of Clinical Investigation.

XLHPT has likely affected family members at least since the 19th century and was initially described in 1960 by Virginia Peden, a faculty member at Saint Louis University. Although there initially seemed to be two separate families afflicted with the disorder, in 1996 researchers were able to scientifically detect signs of a common ancestry between the two family lines.

When it became possible to measure parathyroid hormone in the 1970s, doctors recognized that the families’ male children had very low levels of that hormone in their blood. Produced by the parathyroid gland, the hormone is a regulator of calcium and other materials in the bloodstream.

Once they knew that affected boys had low parathyroid levels, doctors began successfully treating them with high doses of vitamin D that restored calcium levels in their circulatory system. As a result, men affected by XLHPT now have a normal life expectancy.

Whyte and others gradually gained insights into the disorder over the course of the past three decades. In 1986, an autopsy of a patient with the condition revealed that the parathyroid glands were missing and presumably never formed.

“This made it obvious that the genetic changes in these families were somehow disrupting the activities of genes responsible for making the parathyroid glands during embryonic development,” Whyte explains. “Four years later, a team at Oxford led by Dr. Rajesh Thakker determined where those changes were taking place on the X chromosome.”

Thakker, who is the May Professor of Medicine at Oxford, has continued to be involved in efforts to untangle the cause of XLHPT and was senior investigator for the latest study.

When investigators determined that a region of genetic material on the X chromosome had been replaced, they turned to the Human Genome Project for data on what genes were in the missing segment. To their surprise, there were none–the missing region appeared to be a gene desert lacking any information used to make proteins.

Scientists then expanded their search for an explanation and noted that a gene called SOX3 was just a short distance away from the segment removed from the X chromosome. This opened up the possibility that molecules regulating the SOX3 gene’s activity might normally bind to the missing segment of the X chromosome. With that piece of the chromosome gone, SOX3 may not function as it should.

“The investigators at Oxford showed that SOX3 is active in the right area of the mouse embryo and at the right time to be a contributor to development of the parathyroid glands, so that’s a hint that it might be the gene through which the formation of the parathyroid gland is disrupted,” says Deborah Wenkert, M.D., a researcher at Shriners Hospital in St. Louis.

According to Whyte, a complete understanding of how the genetic change is disrupting the formation of the parathyroid glands may one day be useful for researchers working on new treatments for osteoporosis, a bone-weakening condition common in the elderly.

“A fragment of parathyroid hormone is being used to treat osteoporosis right now,” he notes. “Anything that switches on or switches off parathyroid hormone secretion could potentially be useful for treating osteoporosis and perhaps other bone disorders.”