Achondroplasia is a long word describing genetically short people. Their dwarfism results from a mutant gene at an unknown location that normally directs the conversion of fetal cartilage to bone during pregnancy. As a result, achondroplastic dwarfs are born with abnormally short legs and arms on a normal but swayback trunk, large heads with flattened noses, and stubby hands, but completely normal mental abilities.
With an estimated one to 15 achondroplastic dwarfs per 100,000 live births, they make up by far the most common form of dwarfism, said molecular geneticist Petros Tsipouras of the University of Connecticut. He is the principal author of a report in the March issue of Nature Genetics titled "The gene for achondroplasia maps to the telemeric region of chromosome 4p." It appears back-to-back with an almost identical, similarly titled paper by Arnold Munnich of the Hospital for Sick Children in Paris, which is affiliated with France's National Institute of Health and Medical Research.
Huntington's Unknown Gene Neighbor
Chromosome 4 is one of the best-studied in the human genome. It is an unhappy hunting ground for mapping disease- associated genes, most notably the gene for Huntington's disease (HD). In fact, James Gusella of Harvard Medical School, who led the 10-year search for the HD gene, is a co-author of Tsipouras' paper. It tracks the achondroplasia gene to the tip of chromosome 4's short arm, with genetic linkage to three markers at 4pl6.3. That's close to the address of the HD gene, which Gusella et al identified just a year ago after a decade- long search.
Achondroplasia is inherited as an autosomal dominant trait; a single defective gene transmitted by one average-size parent can produce a dwarf offspring. But if both parents are dwarfs carrying such a gene, the child stands a 25 percent chance of getting a lethal double dose (is homozygous) and rarely lives longer than a few months. "A homozygous birth is very rare," Tsipouras told BioWorld, because it means you have to have two heterozygous parents.
Since submitting their paper for publication last fall, the researchers have further narrowed the candidate region on chromosome 4 "to the smallest possible denominator, which will allow us to go in and start the positional cloning process" to locate the gene for achondroplasia.
Tispouras' "educated guess" on finding the gene is that since the HD research marked chromosome 4's distal tip so well, "we'll probably have something within a year."
His optimism is echoed by another key hunter for the achondroplasia positional gene, medical geneticist Clair Francomano of Johns Hopkins University. "Things are happening now so much faster than they ever have before," she told BioWorld. "It could break at any time." Francomano, who is medical director of the Laboratory for Skeletal Dysplasias at Johns Hopkins, added, "It's a little hard to predict, but you can be sure there are people working very hard on it, including us."
Francomano describes achondroplasia as "the commonest cause of short stature in humans and one of the most important remaining genetic diseases to fall to the assignment of gene mapping."
Like Tsipouras and Munnich, she has assigned the still-sought achondroplasia gene to the tip of chromosome 4. "We have recently submitted similar findings for publication, corroborating theirs, and hope our paper will appear in April," she said. Like the other findings, hers are based on restriction fragment length polymorphisms (RFLPs) and linkage analysis of affected individuals in multiple families. Tsipouras' group studied 14 families, Munnich's 15 and Francomano's 18.
To obtain DNA from his 14 families, Tsipouras recalled, "We scraped the bottom of the earth to get those families, of whom there are not that many. They were from the U.S., Canada, Europe and South Africa. Munnich's 15 families -- 41 affected individuals and 35 relatives -- came from three French centers, plus one in Poland. The French study combined cases with frank achondroplasia and others with a milder allelic variant, hypochondroplasia.
Highest Human Mutation Rate
An estimated 80 percent or more of all achondroplastic births result from new mutations PP one of the highest rates in humans. What causes these baffling, sporadic cases is "a million-dollar question," said Tsipouras.
Francomano observed that the cases probably arise at the standard rate of about one in a million nucleotides. When genetically counseling her at-risk patients, Francomano calls these de novo mutations "celestial typos" PP errors in copying DNA during germ-cell meiosis. "Each family has its own," she noted; evidence suggests that they increase with advanced paternal age, as Down's syndrome does in older women.
Francomano serves on the medical advisory board of the Little People of America (LPA) association, a support organization for all forms of short-statured people and their average-size parents. It includes what are popularly called "midgets" as well as dwarfs. The former condition is due to endocrine or pituitary deficiencies, the latter to aberrant bone-growth genes.
LPA says there are more than 100 types of dwarfs and that medical complications occur in all types, requiring multispecialty medical treatment. The association cooperates with the research of Tsipouas and Francomano, and through its French counterpart, with Munnich.
Because achondroplasia is so often sporadic in its occurrence rather than predictably inherited like, say, cystic fibrosis, prenatal diagnosis and genetic counseling have limited scope. But "once we understand what the actual gene is, we can start thinking in biotechnology terms about what we can do in the long run, not only from the preventive side, but also from the therapeutic," Francomano said.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.