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(The Scientist, Vol:10, #6, p. 14, March 18, 1996) R. Shiang, L.M. Thompson, Y. Zhu, D.M. Church, T.J. Fielder, M. Bocian, S.T. Winokur, J.J. Wasmuth, "Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia," Cell, 78:335-42, 1994. (Cited in more than 70 publications as of February 1996) Comments by Leslie M. Thompson and Rita Shiang, University of California, Irvine The past decade or so has seen the discovery of a number of disease gene

By | March 18, 1996

(The Scientist, Vol:10, #6, p. 14, March 18, 1996)

R. Shiang, L.M. Thompson, Y. Zhu, D.M. Church, T.J. Fielder, M. Bocian, S.T. Winokur, J.J. Wasmuth, "Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia," Cell, 78:335-42, 1994. (Cited in more than 70 publications as of February 1996)

Comments by Leslie M. Thompson and Rita Shiang, University of California, Irvine

The past decade or so has seen the discovery of a number of disease genes. This paper adds another gene to the list. In this case, researchers at the University of California, Irvine, taking advantage of a decade-long hunt for the Huntington's disease gene, found a nearby gene mutation that causes achondroplasia, the most common genetic form of dwarfism.

David Wasmuth
GENE-FINDER: UC-Irvine gene researcher John Wasmuth, who died last year, led the team that found a dwarfish gene.
In 1994, several reports linked achondroplasia to a region near the Huntington's disease gene on chromosome 4 (C.A. Francomano et al., Human Molecular Genetics, 3:787-92, 1994; M. Le Merrer et al., Nature Genetics, 6:318-21, 1994; M. Velinov et al., Nature Genetics, 6:314-7, 1994). One of the gene candidates in that region was fibroblast growth factor receptor 3 (FGFR3).

The team, led by John J. Wasmuth, a UC-Irvine professor of biological chemistry who died last year, found the defective gene just six weeks after beginning its gene hunt. The search was accelerated because his lab had intensively studied the FGFR3 gene three years before as part of a collaborative effort to find the Huntington's disease gene.

In this paper, researchers "detected a glycine-to-arginine transition in the gene coding for FGFR3, resulting in an amino acid change in the transmembrane domain of the protein," explains Leslie M. Thompson, a research associate at UC-Irvine. The receptor is one of a family of FGF receptors that mediate cellular responses in many tissues, including developing cartilage. "Ninety-five percent of achondroplasia is caused by this specific change," notes Rita Shiang, also a research associate at UC-Irvine. Both Shiang and Thompson contributed equally to the work.

Shiang and Thompson
CURIOUS: UC-Irvine scientists Rita Shiang, left, and Leslie Thompson, with their colleagues, continue to study how a gene mutation causes dwarfism.
"This glycine-to-arginine alteration in the protein somehow interferes with or activates cell signaling, though we're not sure how it does so," Thompson says. The researchers plan to continue to study how the mutation affects cellular signaling, and ultimately how the mutation causes achondroplasia. They theorize that the gene mutation is turned on fairly early in development. Scientists are developing mouse models to study the mutation.

Thompson and Shiang believe that the paper is cited frequently because it was the first to identify a growth factor receptor mutation responsible for a skeletal dysplasia. Now researchers are finding such mutations involved in a number of similar diseases.

One result of the work is a simple rapid-screening test for identifying common mutations. Thompson is quick to point out that such a screen would be used only for prenatal testing of pregnancies at risk of having two copies of the gene mutation, which is invariably fatal. The achondroplasia gene is autosomal dominant-one copy of the genetic mutation is required for the disease. Achondroplasia affects about one in 20,000 people, causing alterations in bone growth and development and resulting in an enlarged head, normal-sized trunk and short limbs.

Another paper that contributed to the achondroplasia gene mutation discovery, Thompson notes, is L.M. Thompson et al., Genomics, 11:1133-42, 1991, in which the FGFR3 gene was isolated as a candidate for Huntington's disease.

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