LONDON ¿ The gene responsible for a rare form of dwarfism has been pinned down by an international collaboration of geneticists. Families belonging to the Amish community in Lancaster County, Pa., as well as pedigrees from Brazil, Italy and the UK, all helped to contribute information leading to the detection of the gene that causes Ellis-van Creveld syndrome.
The same study found that a related condition called Weyers acrodental dysostosis, which is also very rare, is caused by mutations in the same gene, now called EVC.
Ellis-van Creveld syndrome, first described in 1940, involves short stature, including short ribs and short limbs, as well as extra little fingers and toes. Abnormal development of the knees causes pain and disability. Many people with the condition also are born with a heart defect, where the septum between the right atrium and the left atrium is either missing or defective. This proves fatal in some cases, but in others it can be repaired surgically. People with Weyers acrodental dysostosis also have skeletal and cardiac abnormalities, but these usually are milder than in Ellis-van Creveld syndrome.
The story of the discovery of the gene is told in a paper in the March 2000 issue of Nature Genetics, titled ¿Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.¿ Judith Goodship, senior lecturer in the department of human genetics at Newcastle University, told BioWorld International: ¿I became interested in this project because I was interested in heart abnormalities and how the heart develops. I thought it would provide clues to how the septum between the atria forms.¿
Goodship, who is senior author of the Nature Genetics paper, formed a collaboration with two other main groups: one led by Mihael Polymeropoulos, previously of the National Institutes of Health in Bethesda, Md., but currently of Novartis Pharmaceuticals in Gaithersburg, Md., and one led by Thomas Meitinger, of Ludwig-Maximilians-Universitat in Munich, Germany.
Researchers from the National Human Genome Research Institute at the National Institutes of Health; George Washington University in Washington, D.C.; the University of Bremen in Bremen, Germany; the Ospedale Pediatrico Bambino Gesu in Rome, Italy; and La Sapienza University in Rome also took part in the study.
By 1996, the initial collaborators had mapped the gene responsible for Ellis-van Creveld syndrome to the short arm of chromosome 4. Goodship said, ¿We knew it was in quite a large region, two megabases in size. At the same time, we were looking for additional families that would help us to pinpoint the exact position of the gene.¿
The researchers initially could not find any mutations among the Amish families they were studying. Progress speeded up, however, once parts of the sequence of chromosome 4 became available on the Internet from the Human Genome Project at Stanford University in Stanford, Calif.
The first breakthrough came when the team identified a mutation in a woman affected by Ellis-van Creveld syndrome, who came from the remote Scottish isle of Barra. Goodship told BioWorld International, ¿We can speculate that a mutation had occurred in a distant ancestor, whose descendents had eventually intermarried.¿ The big advantage with cousin marriages, she pointed out, is that the same genetic abnormality has to be present in both parents, making it easier to find.
Other mutations in other affected individuals were picked up soon after. In the Amish families, two changes were identified after the entire coding sequence of the candidate gene had been sequenced. One of these changes was thought to be a normal polymorphism; the same change also was found in a British control. The other was a mutation that had the effect of altering the splicing of the transcribed gene. Both of these changes were found in all affected individuals of this family (which had nine branches), but not in those individuals who were not affected.
The team still has not found a mutation in the Brazilian pedigree, nor in two families where the parents were related. In each of these pedigrees, the affected individuals were homozygous across the region, the researchers report in their paper. They did, however, find many polymorphisms, and the paper reports those that have the effect of changing the amino acid sequence of the protein.
Exactly what the role of the protein encoded by EVC is remains to be discovered. Goodship told BioWorld International: ¿It¿s a completely new protein and we want to know what it does ¿ that is our work for the next three years.¿ This will not be easy, she added, as the protein is only expressed in developing tissues. Initial investigations by the team have shown that it is expressed in human embryonic tissue at low levels in developing bone, heart, kidney and lung.
The paper reports: ¿In bone, EVC was expressed in the developing vertebral bodies, ribs and both upper and lower limbs. The expression was higher in the distal limb compared with the proximal limb. In addition, we detected EVC expression in the branching epithelium and surrounding mesenchyme of the lung, metanephros and atrial and ventricular myocardium, including both atrial and interventricular septa.¿
One of the surprises for the research team was the discovery that some patients who had mutations in the EVC gene did not have physical abnormalities typical of the syndrome. ¿The spectrum of problems caused by this gene may be a lot wider than previously thought,¿ Goodship said.
What is the significance of the finding? Goodship said: ¿In the short term, it does not alter how clinicians can look after people affected by these syndromes. It may eventually tell us quite a lot about how the heart and skeleton normally develop. Some families, having had one child with Ellis-van Creveld syndrome, may choose to opt for prenatal diagnosis in a subsequent pregnancy, which is now possible, following this discovery. But many affected families would not want that because they do not perceive the condition to be sufficiently severe to warrant termination of affected pregnancies.¿