Achondroplasia is a long word describing genetically shortpeople. Their dwarfism results from a mutant gene at anunknown location that normally directs the conversion of fetalcartilage to bone during pregnancy. As a result, achondroplasticdwarfs are born with abnormally short legs and arms on anormal but swayback trunk, large heads with flattened noses,and stubby hands, but completely normal mental abilities.
With an estimated one to 15 achondroplastic dwarfs per100,000 live births, they make up by far the most commonform of dwarfism, said molecular geneticist Petros Tsipouras ofthe University of Connecticut. He is the principal author of areport in the March issue of Nature Genetics titled "The genefor achondroplasia maps to the telemeric region of chromosome4p." It appears back-to-back with an almost identical, similarlytitled paper by Arnold Munnich of the Hospital for SickChildren in Paris, which is affiliated with France's NationalInstitute 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'sdisease (HD). In fact, James Gusella of Harvard Medical School,who led the 10-year search for the HD gene, is a co-author ofTsipouras' paper. It tracks the achondroplasia gene to the tip ofchromosome 4's short arm, with genetic linkage to threemarkers 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; asingle defective gene transmitted by one average-size parentcan produce a dwarf offspring. But if both parents are dwarfscarrying such a gene, the child stands a 25 percent chance ofgetting a lethal double dose (is homozygous) and rarely liveslonger than a few months. "A homozygous birth is very rare,"Tsipouras told BioWorld, because it means you have to havetwo heterozygous parents.
Since submitting their paper for publication last fall, theresearchers have further narrowed the candidate region onchromosome 4 "to the smallest possible denominator, whichwill allow us to go in and start the positional cloning process" tolocate the gene for achondroplasia.
Tispouras' "educated guess" on finding the gene is that sincethe 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 theachondroplasia positional gene, medical geneticist ClairFrancomano of Johns Hopkins University. "Things arehappening 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 SkeletalDysplasias 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 causeof short stature in humans and one of the most importantremaining genetic diseases to fall to the assignment of genemapping."
Like Tsipouras and Munnich, she has assigned the still-soughtachondroplasia gene to the tip of chromosome 4. "We haverecently 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 restrictionfragment length polymorphisms (RFLPs) and linkage analysisof affected individuals in multiple families. Tsipouras' groupstudied 14 families, Munnich's 15 and Francomano's 18.
To obtain DNA from his 14 families, Tsipouras recalled, "Wescraped the bottom of the earth to get those families, of whomthere are not that many. They were from the U.S., Canada,Europe and South Africa. Munnich's 15 families -- 41 affectedindividuals and 35 relatives -- came from three French centers,plus one in Poland. The French study combined cases withfrank achondroplasia and others with a milder allelic variant,hypochondroplasia.
Highest Human Mutation Rate
An estimated 80 percent or more of all achondroplastic birthsresult from new mutations PP one of the highest rates inhumans. What causes these baffling, sporadic cases is "amillion-dollar question," said Tsipouras.
Francomano observed that the cases probably arise at thestandard rate of about one in a million nucleotides. Whengenetically counseling her at-risk patients, Francomano callsthese de novo mutations "celestial typos" PP errors in copyingDNA during germ-cell meiosis. "Each family has its own," shenoted; evidence suggests that they increase with advancedpaternal age, as Down's syndrome does in older women.
Francomano serves on the medical advisory board of the LittlePeople of America (LPA) association, a support organization forall forms of short-statured people and their average-sizeparents. It includes what are popularly called "midgets" as wellas dwarfs. The former condition is due to endocrine or pituitarydeficiencies, the latter to aberrant bone-growth genes.
LPA says there are more than 100 types of dwarfs and thatmedical complications occur in all types, requiringmultispecialty medical treatment. The association cooperateswith the research of Tsipouas and Francomano, and through itsFrench counterpart, with Munnich.
Because achondroplasia is so often sporadic in its occurrencerather 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 startthinking in biotechnology terms about what we can do in thelong run, not only from the preventive side, but also from thetherapeutic," Francomano said.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.