Researchers identify clue to genetic cause of fatal birth defect

Washington, Oct 10 : An enzyme may play a major role in anencephaly, offering hope for a genetic test or even therapy for the rare fatal birth defect in which the brain fails to develop, according to a study.

In US 1,000 to 2,000 children are born with anencephaly each year. Most do not survive more than a day or two. Although anencephaly can sometimes be diagnosed through ultrasound, which picks up the malformation of the head, there is no genetic test, and its cause is unknown.

By breeding special "knockout" mice that were missing the gene for the enzyme called HSD17b7, University of Illinois (UIC) researchers found that such mice died on the 10th day of gestation with the severe lack of brain development that characterizes the human birth defect.

The failure of the mice to develop, as well as the extreme nature of the changes in the formation of the animals, was very surprising, said Geula Gibori of UIC College of Medicine and principal investigator of the study.

UIC researchers had previously discovered this novel enzyme and were focussed on its role in converting the weak hormone oestrogen into the more potent estradiol in the ovaries and its possible role in breast cancer, according to an UIC press release.

Recent research has shown that the HSD17b7 enzyme has an additional role in the last steps of cholesterol biosynthesis. But because the foetus receives cholesterol from the mother during gestation, Gibori and her colleagues did not expect the enzyme to be of much importance to development, she said.

However, it appears that as the foetal mouse brain develops it forms a blood barrier, blocking maternal cholesterol from brain cells. The brain becomes dependent on the biosynthesis of its own cholesterol once this blood-brain barrier forms, at day 10 of gestation.

The UIC researchers established that in the foetus, the brain is the most important site for HSD17b7 expression and provided evidence that anencephaly may result from the loss of this enzyme.

The study appeared in the October issue of Molecular Endocrinology.