Diastrophic dysplasia

It's been a good summer for little people. Scientists have now tracked down the genetic bases of two more skeletal abnormalities underlying short stature, information that can aid genetic testing and perhaps lead to the prevention of, or treatments for, dwarfism.

Most recently, a multidisciplinary U.S.-Finnish team used a new analytical technique called fine-structure linkage disequilibrium mapping to determine the cause of diastrophic dysplasia (DTD). DTD causes most of the dwarfism in Finland and is the third most common form in the United States. People who inherit two defective DTD genes develop twisted bones and arthritis, says Johanna Hastbacka of the Whitehead Institute for Biomedical Research in Cambridge, Mass.

Most of the 5 million Finns descended from a small group that 2,000 years ago settled what is now Finland. Thus, Hastbacka, Whitehead colleague Eric S. Lander, and Albert de la Chapelle of the University of Helsinki assumed that the defective DTD gene most likely arose from one person in that group.

The researchers first examined the genetic codes of affected members of 18 families with this disease and from that narrowed their search to an end of chromosome 5. They then analyzed the genetic material of 77 Finnish families having at least one member with a DTD gene, looking for ever smaller regions of that chromosome common to all these individuals. That common section represents the remains of the original ancestor's chromosome bearing this defective gene, Hastbacka says.

The DTD gene codes for a protein similar to ones already known to exist in rats and a fungus. Those proteins transport sulfate in and out of cells. Tissue taken from people with DTD does not take up enough sulfate, the group reports in the Sept. 23 CELL. Without sugar sulfate compounds, cells that make bone cannot lay down material that is both tough and resilient, she adds.

This summer, John J. Wasmuth of the University of California, Irvine, and his colleagues reported finding the gene that is defective in achondroplasia, the commonest genetic form of dwarfism in most parts of the world. That gene, called fgfr3, lies on one end of chromosome 4. Its protein product sits on the surfaces of cells and binds to specific growth factors, the group reported in the July 29 CELL. They found the gene quickly because they had first studied it as a possible candidate in Huntington's disease, Wasmuth says.

In achondroplasia, limbs are too short and the head is too large. A single amino acid change in the fgfr3 protein seems responsible, says Arnold Munnich of the Necker Institute at the Hospital for Sick Children in Paris. When he and his colleagues examined the DNA sequence of the fgfr3 gene in people with the growth disorder, they found that one nucleotide had been replaced by another. As a result, part of the protein that runs through a cell membrane contains an arginine amino acid where normally a glycine lies, Munnich and his colleagues report in the Sept. 15 NATURE. They found this amino acid switch in six unrelated individuals with achondroplasia in their heritage and in 17 sporadic cases -- in which parents spontaneously developed the genetic defect and passed it on to their children.

COPYRIGHT 1994 Science Service, Inc.
COPYRIGHT 2004 Gale Group