LONDON — A second gene that is responsible for some cases of Parkinson's disease has been tracked down by researchers in Europe.

In two of the families studied, both of which come from northern Germany, affected individuals have inherited the same chromosomal fragment, suggesting they may share a distant common ancestor.

The research group is now searching for mutations in a candidate gene in the chromosomal region which is co-inherited with the disease. The gene codes for transforming growth factor alpha, which is known to have trophic effects on dopaminergic neurons.

Thomas Gasser, neurologist at the Grosshadern Clinic at the Ludwig-Maximilians University, in Munich, Germany, told BioWorld International: "If we are lucky we will have the results within a week or two. We want to find out if affected family members have mutations in this gene which are not shared by family members who are not affected."

Gasser, together with colleagues in Munich, Hamburg and Lubeck, Germany, and in Rome, Omaha, Neb., and Vancouver, British Columbia, reported the results in a letter published in the March 1998 issue of Nature Genetics, titled "A susceptibility locus for Parkinson's disease maps to chromosome 2p13."

Gasser and Bertram Muller-Myhsok, of the Bernhard-Nacht-Institute for Tropical Medicine, in Hamburg, are joint first authors of the letter.

The discovery of this second gene follows that of a first by Robert Nussbaum, of the National Human Genome Research Institute, in Bethesda, Md., and colleagues last year. Nussbaum's group mapped the locus they identified to chromosome 4q21. Affected members of the families they studied suffered symptoms of Parkinson's disease which in general corresponded to those experienced in sporadic cases, except that in these families the mean age of onset was younger than usual, at 46 years, and the progression of the disease was rapid, with only 10 years from onset to death.

Since this finding, however, it has become clear the gene on 4q21 is not linked to many of the familial cases of Parkinson's disease, and that none of the sporadic cases examined are associated with it.

Unlike the pedigrees studied by Nussbaum and colleagues, the affected members in the families studied by Gasser, Muller-Myhsok and colleagues have a mean age of onset of Parkinson's disease that is very similar to that of sporadic cases of Parkinson's disease: 59 years compared with 59.7 years, respectively.

Gasser doubted any of the familial genes responsible for Parkinson's disease will turn out to be directly involved in sporadic cases of the disease, but agreed that finding out what these genes are will shed light on the pathogenesis of the disease.

Research Focused On Danish, German Families

The European group studied six families in which Parkinson's disease was inherited as an autosomal dominant trait. A genome screen of the two largest families suggested that an area of chromosome 2 was co-inherited with the disease, and more detailed investigation of this locus in all six families provided statistically significant evidence that a gene in this region was indeed linked to the disease.

Gasser added: "In two of the families originating from northern Germany, we found evidence that both families shared a small part of this chromosomal region. This might be evidence for a founder effect, suggesting that they both have a common ancestor."

The ancestors of both families originated from neighboring regions of southern Denmark and northern Germany.

The group is now studying smaller families, particularly those from northern Germany, to see whether the same chromosomal region is linked to the disease in them as well.

"This would be one way of confirming the finding that there really is a causative gene in this chromosomal region," Gasser said.

Although the team has gone ahead with searching for mutations in the gene coding for transforming growth factor alpha, Gasser said they have no real idea about what kind of gene will turn out to be involved. The chromosomal region concerned is very large, about 10 centimorgans, and there may be 100 or more genes within it.

One way to narrow down the search for the gene responsible would be to find linkage of this region with the disease in a different population. Gasser said: "This could help us refine the region further."

He concluded: "We can only hope that when we find out which gene is involved, this will lead to better understanding of the molecular pathogenesis of Parkinson's disease, which will one day help in designing more rational therapy."

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