By Sharon Kingman

Special To BioWorld Today

LONDON * A gene which may account for some cases of short stature, including the short stature typical of Turner's syndrome, has been identified by a team of German and Japanese scientists. They believe that the discovery may one day make it possible to devise new treatments for short stature by correcting the genetic defect involved.

Gudrun Rappold, of the Institute of Human Genetics at Heidelberg University, in Heidelberg, Germany, and her colleagues report in the May issue of Nature Genetics that the newly identified gene may be responsible for between 1 percent and 2 percent of cases of short stature of unknown cause. In their paper, titled "Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome," they say their discovery "paves the way for a deeper understanding of the biological processes involved in growth control."

Growth failure affects about three in 100 people. Although some cases have known causes such as growth hormone deficiency, most have no known cause and are classified as "idiopathic" short stature.

In searching for genes responsible for short stature, researchers have focused their efforts on the sex chromosomes, because sex chromosome abnormalities are sometimes associated with abnormal growth patterns. Individuals with Turner's syndrome, for example, who have only one X chromosome, have short stature as well as other abnormalities, such as streak gonads, webbed neck and heart defects. In addition, several studies have shown that deletion of the short arms of either the X or the Y chromosomes consistently lead to short stature.

Rappold and her colleagues started their search by examining the extent of the deletion from the tip of the X chromosome in a large group of people, including many of short stature, and correlating this with each individual's height. This allowed them to pinpoint the region in which the gene or genes responsible lay.

They went on to identify a gene which they called SHOX, for short stature homeobox-containing gene. Genes containing a homeobox have a fundamental role in human development; they are, for example, expressed in early embryonic development.

Further studies by the team showed that people of normal height had two copies of the SHOX gene, while those of short stature had only one copy of SHOX. They identified two different forms of the gene, and found that the expression profile of these two forms varied. For example, SHOXa is widely expressed in most tissues, while SHOXb is mainly expressed in bone marrow fibroblasts.

Rappold told BioWorld Today: "To prove that this gene really does underlie short stature, we screened 91 patients with short stature and we found that one out of the 91 had a mutation in SHOX." This suggests, Rappold said, that SHOX is one of the important genes influencing height.

The mutation identified resulted in a truncated protein, and the same mutation was absent from 300 other individuals of normal height. Study of the pedigree of the patient with the mutation showed that it was present in those family members who had inherited short stature, but absent in those of normal height.

The exact function of the gene product is not known. "We do know that it is a transcription factor. This means it is likely to bind to DNA and activate transcription. We need to find out which proteins the gene is interacting with, and we are working on defining these at the moment," she said.

Large-scale studies to find out how commonly the gene is absent from or mutated in people of short stature are now under way.

Rappold adds that the group's major goal now is to try to develop new therapeutic strategies for the treatment of short stature in Turner's syndrome and for people with short stature caused by mutation or loss of the SHOX gene. Patients with Turner's syndrome do respond to very high doses of growth hormone given over a long period, and Rappold suggests that people in the second category may also benefit from such treatment.

But this treatment is very unspecific, she points out, and because it only began to be prescribed about 10 years ago, no one can be sure what the long-term side effects might be.

"It does not take into account the genetic cause of the short stature, but we think that we have now found that cause, and hopefully we can design more targeted therapies in the future," Rappold said. "This will also improve the outlook for a proportion of patients with idiopathic short stature."

She hopes that the development of knockout mice will assist in unraveling the biological function of SHOX and speed the development of new therapies. *