Using a combination of history, population genetics and computational biology, a joint team of US and Finnish scientists has discovered the gene responsible for the third most common form of dwarfism in the United States, and the most common form in Finland.
This unique piece of genetic detective work is important not only because it reveals the mechanism of the disease, diastrophic dysplasia (DTD)-and suggests a possible new direction for therapy-but also because it introduces a new method for tracking down human disease genes. The new method, called "linkage disequilibrium mapping," is described in the cover story of the September 23 issue of Cell.
It is useful in any population in which it is possible to trace chromosomes descending from a common ancestor. Possible examples include the Cajun population in the United States, certain groups of French Canadians, and isolated island populations in Japan and many other countries.
Dr. Johanna Hastbacka, a postdoctoral fellow at the Whitehead Institute for Biomedical Research and first author of the Cell paper, explained that the Finnish population of 5 million is largely descended from a small "founder" population that began to expand some 2,000 years ago. The researchers took advantage of this unusual history to find the cause of DTD, a form of dwarfism associated with twisted, misshapen bones and painful, early-onset arthritis.
Dr. Hastbacka and her colleagues, led by MIT Professor Eric Lander of the Whitehead Institute and Dr. Albert de la Chapelle of the University of Helsinki, suspected that most Finnish cases of DTD originated with one member of the founder population. The single mutation responsible for the disease had been passed from generation to generation for 2,000 years.
The investigators searched for telltale spelling differences in the genetic code of today's DTD patients to find the historical remnant of the ancestral chromosome bearing the disease gene. This strategy allowed them to narrow the search for the DTD gene 100 times more precisely than would have been possible with more conventional genetic tools. The unusual search led to a tiny piece of human chromosome 5, and then rapidly, to the DTD gene itself.
Analysis of the gene showed that it encodes a protein involved in sulfate metabolism. This finding suggests new directions for research on DTD therapy. Future studies will explore whether it may be possible to boost sulfate transport into affected cells, and thereby alleviate some of the chronic skeletal problems associated with this disabling disease.
Mary Carten, former president of Little People of America, Inc., and co-editor of Diastrophic Dynamics, said that the discovery of the DTD gene is especially exciting because the disease generally has not received as much attention in the research community as achondroplasia, the most common form of dwarfism in the United States.
"This discovery gives us something to look forward to," she said. "It may not help those of us with DTD now, but someday it may lead to new therapies for babies diagnosed in the womb, or suggest a way to improve bone growth after birth.
"The discovery of the gene will also lead to better diagnosis of the disease and help us reach more parents of affected children-to provide the medical and emotional support that will allow these children to lead full and productive lives even before the development of new therapies," Ms. Carten said.
In the future, the US and Finnish scientists intend to use the strategy developed for DTD to search for genes associated with more common diseases, including breast cancer, diabetes, asthma and systemic lupus erythematosus. This long-term collaboration, called "The Finland Project," will be directed jointly by Dr. Juha Kere of Helsinki University, Dr. de la Chapelle and Dr. Lander.
This work was supported in part by grants from the National Institutes of Health, the Markey Foundation, the Academy of Finland and the Juselius Foundation.
In addition to Drs. Hastbacka, Lander and de la Chapelle, this project included a dozen geneticists, biochemists, and physicians from MIT as well as scientists from the Whitehead Institute; the Department of Medical Genetics at the Univeristy of Helsinki and Folkhalsan Institute of Genetics; the Department of Medical Genetics at Helsinki University Central Hospital; the Department of Neurogenetics at Massachusetts General Hospital, and the Department of Biochemistry and McDermott Center at the University of Texas Southwestern Medical Center in Dallas.
A version of this article appeared in the September 28, 1994 issue of MIT Tech Talk (Volume 39, Number 6).