Diagnostics & Imaging Week Correspondent

LONDON The discovery in Dutch women of a mutant gene that causes pre-eclampsia a common disease of pregnancy that threatens the health of both mother and fetus might soon provide clinicians with the means to test newly pregnant women to establish their risk.

Establishing the normal function of the gene, which is called STOX1, also will help researchers to develop therapies to treat the condition.

Cees Oudejans, head of the molecular biology laboratory in the department of clinical chemistry at the VU University Medical Center (Amsterdam, the Netherlands), told Diagnostics & Imaging Week: "In the future, it may be possible to offer women some form of prenatal diagnosis during the first trimester and identify those who are guaranteed not to develop pre-eclampsia, as well as those with a 50:50 chance of getting it. That will allow doctors to provide better monitoring and guidance of pregnancies in women at high risk."

Oudejans said that women in other parts of the world probably develop pre-eclampsia due to other mutations, but that it is likely that those affect the same biochemical pathway as does the mutation in STOX1. STOX1 is on chromosome 10, but researchers in Iceland and Australia, for example, have been focusing on genes located on chromosomes 2 and 4. Oudejans urged researchers to narrow their search to genes that operate in the same pathway as STOX1.

He and his colleagues reported their work in the April 3, 2005, issue of Nature Genetics in a paper titled "Maternal segregation of the Dutch pre-eclampsia locus at 10q22 with a new member of the winged helix gene family."

Pre-eclampsia occurs when the connection between the placenta and the maternal blood vessels fails to form properly, beginning in the first trimester of pregnancy. Only much later in the pregnancy does the mother start to show symptoms, which include hypertension and secretion of protein into the urine.

The only effective cure is delivery of the baby, which is not always possible.

Pre-eclampsia is the most common disease of pregnancy in developed countries, affecting between 5% and 10% of pregnancies, depending on how it is defined. It causes both morbidity and mortality in both mother and fetus: The clinician caring for the pregnant woman must weigh the risk to the fetus of ending the pregnancy prematurely against the risk to the mother's health of continuing it.

Oudejans and his colleagues had access to DNA from a large cohort of sisters with pre-eclampsia, collected in the Netherlands by Augusta Lachmeijer. Using conventional linkage analysis, she had narrowed the search for a "pre-eclampsia gene" down to chromosomes 10 or 22.

Subsequently, Oudejans and his team went on to establish that the gene they were looking for was on chromosome 10. They also noticed that the sisters who had pre-eclampsia always shared certain chromosomal sequences with each other that they had derived from their mothers.

Oudejans said: "So we had a 'parent of origin' effect. In other words, expression of this genetic material depended on which parent it was derived from. It turned out that the genetic information in this region that these sisters had inherited from their fathers was not important at all."

They set out to determine if there was a gene located in the area of interest on chromosome 10, that is expressed in the placenta and that is expressed preferentially when it is inherited from the mother. After much research, including sequencing 17 genes from 16 patients, they had the answer: STOX1. All the families in Lachmeijer's cohort had mutations in the gene, and the mutations always were identical between affected sisters of the same family.

Further studies established that STOX1 is transcribed in early placenta. The gene, which encodes a DNA-binding protein, is related to the forkhead (FOX) family.

The team now is examining how to combine their finding with early prenatal diagnosis.

Oudejans said: "In my lab, we provide non-invasive prenatal diagnosis using fetal RNA in maternal blood. We now want to know if there is more or less RNA of this particular gene in the blood of those women who get pre-eclampsia later in pregnancy. It may also be possible to look for fetal DNA, which in the first trimester of pregnancy is mainly from the placenta, and detect the mutations that we found."