COLUMBUS, Ohio - After a 10-year search, an international team of scientists has identified the gene responsible for the most common form of dwarfism. The team, led by Ohio State University researchers and colleagues from Finland and Holland, reported their discovery in latest issue of the journal Cell.
The finding should enable doctors to identify carriers of the genetic mutations, may lead to a better understanding of dwarfism generally, and may someday lead to a treatment for the disease. Mutations in this gene cause a syndrome known as cartilage-hair hypoplasia, or CHH, a rare disease that occurs worldwide but is particularly prevalent in Finnish and Amish populations. Among the Amish, including those in Ohio and Pennsylvania, researchers estimate that one in 19 people carry the mutations, while among Finns, one in 76 are thought to carry them.
The syndrome has other abnormalities as well. These can include a greatly enlarged colon; immune deficiency and susceptibility to infections; and a predisposition to lymphoma and certain other cancers.
"Our finding is an important first step in understanding how this disease arises," said Albert de la Chapelle, senior author of the paper and director of the Ohio State's Human Cancer Genetics Program.
The researchers traced the mutations to a gene known as RMRP, a result that came as an enormous surprise because of the nature of the gene.
The RMRP gene belongs to a class known as "untranslated genes." The product of the RMRP gene, a length of RNA, combines with several protein molecules to form an enzyme. The cell then uses that enzyme to process other molecules of RNA.
"This is the first time that an untranslated, nuclear gene has been found to cause a human disease," said de la Chapelle. "We spent several months proving that these mutations were linked to the disorder because we couldn't really believe it ourselves."
The researchers studied more than 100 CHH families and spent two years sequencing, or identifying, the DNA units, or base-pairs, to track down the gene responsible for syndrome.
CHH is a recessive trait. That means two copies of the defective gene must be present in the fertilized egg for the disease to occur. When two people with mutated genes marry, they have a one-in-four chance that their child will have CHH. Exactly how the mutations in the RMRP gene cause CHH, however, is still unknown.
The syndrome is called cartilage-hair hypoplasia because it affects the growth plates of the cartilage, preventing normal bone growth. The word "hair" is included because affected people have hair that is fine, blond, and very brittle, said de la Chapelle.
The Ohio State research team is now working to understand whether different mutations of the RMRP gene cause different degrees of the disease. They want to know, for example, whether some mutations are more likely to lead to cancer or to an immune deficiency.
The question is important because the severity of the disease varies strongly between patients and even within the same family. For example, de la Chapelle said, "siblings with the syndrome can be quite different in height, or one can have an absolutely normal immune system and the other can be seriously immune-compromised. In some cases, there are profound differences."
These variations can arise even though the siblings carry the same mutations in the RMRP gene. For these reasons, he said, "there must be modifying factors that influence the severity of the disease." The researchers suspect that other still unknown genes are also involved.
In addition, de la Chapelle's research team is working to better understand the biochemistry of the disease, what goes wrong at the molecular level, in the cell to cause the disease.
This work was supported through grants and support by the U.S. National Institutes of Health, Academy of Finland, the Ulla Hjelt Fund, Sigrid Juselius Foundation, March of Dimes Birth Defects Foundation andHeslinki University.
Contact: Albert de la Chapelle, (614) 688-4781;
delachapelle-1@medctr.osu.edu
Written by Darrell E. Ward, (614) 292-8456;
Ward.25@osu.edu
Journal
Cell