Some baby girls with Turner's syndrome beat the odds. All male fetuses missing the X chromosome--the syndrome's underlying cause--are spontaneously aborted, as are 97% of female fetuses, which have a backup copy of the sex chromosome. But the survivors can't beat the syndrome's hallmark feature, extremely short stature. Now scientists know why: Two copies of a critical gene appear to be needed for normal growth, and Turner's survivors have only one. The finding, reported in next month's issue of Nature Genetics, suggests a research strategy that may one day help young girls with the syndrome reach full growth.
A team led by Gudrun Rappold, a geneticist at Heidelberg University in Germany, didn't have Turner's survivors in mind when setting out to find genetic abnormalities that might explain why 2% to 3% of all people are much shorter than their peers. The group examined a section of DNA known to be mutated in some short people; the section lay in a so-called pseudoautosomal region (PAR) that is identical in the X and Y chromosomes. By comparing PARs from 16 short individuals, the researchers homed in quickly on a small mutated segment within a single gene, which they dubbed SHOX. They found a point mutation in the gene (a single altered base pair) in one of 91 randomly selected short individuals, and no such mutations in 300 people of average height--suggesting that about 1% of all short people may carry a SHOX mutation. Consistent with the gene's possible role in growth, SHOX contains a homeobox sequence, which means that the protein encoded by the gene is one that regulates the expression of other genes.
Based on this discovery, Rappold speculates that people with Turner's syndrome are short because they have only a single working copy of SHOX. The key to this theory is that the female body turns off one copy of the X chromosome--with the exception of genes located in PARs. Thus, cells appear to require a double dose of PAR-gene proteins to function normally. Turner's females, like people with a SHOX point mutation, have only a single working copy of SHOX.
"It's quite likely that [SHOX's absence] does explain a significant amount of the growth retardation in Turner's syndrome," says Andrew Zinn, a geneticist and Turner's syndrome expert at the University of Texas Southwestern Medical Center in Dallas. Finding a way to boost SHOX expression--either through gene therapy or drugs that act on the existing copy--might lead to a treatment for young girls with the syndrome, Zinn says.