GENETIC MUTATIONS LINKED TO RARE METABOLIC DISEASE
COLUMBUS, Ohio -- Researchers have identified two mutations in a single gene as the cause of a very rare metabolic disease that affects people in Finland, Norway and Saudi Arabia. It has taken nearly 40 years since the identification of the disease for researchers to trace its cause back to a faulty gene.
An international team of a dozen scientists, including those from Ohio State University, reported their discovery in the latest issue of the journal Nature Genetics.
Called megaloblastic anemia 1, or Imerslund-Grasbeck syndrome after the two researchers who first described it, the defects prevent the normal absorption of vitamin B-12. If left untreated, the disease can be fatal. While serious, the syndrome is exceedingly rare -- only one person in a million may develop this disease. The disease has also been identified in patients from Israel, Turkey, Kuwait and the United States as well.
For this study, scientists mapped the DNA of 17 Finnish patients who had the disease, comparing it to disease-free control subjects. They also looked at DNA samples from patients in Norway, as well as members of a Bedouin family in Saudi Arabia, all of whom had the disease.
Researchers have known that the disorder was autosomally recessive, that is, it occurs only when a child inherits a bad copy of the gene from each parent. People who inherit a single bad gene are still able to metabolize vitamin B-12. Normally, vitamin B-12 binds to another compound in the body called intrinsic factor to form a chemical complex the body can use.
But the gene mutation alters the three-dimensional structure of the protein cubilin thats required to make that complex, explains Ralf Krahe, an assistant professor of microbiology and immunology and a researcher with Ohio States Comprehensive Cancer Center.
This is a very subtle change. It doesnt completely destroy the protein -- it just changes a particular amino acid, proline, to leucine.
The actual shape of protein molecules plays a major role in how they function. Proline normally causes a bend in the protein molecule at a specific place and in a specific direction. When the leucine was substituted for the proline, no bend was produced and the molecule malfunctioned.
This major Finnish mutation, called FM1, is responsible for 91 percent of the disease chromosomes studied during the project. The researchers also discovered a minor Finnish mutation, dubbed FM2, which, when the two are considered together, accounts for 97 percent of the mutant Finnish chromosomes. Both mutations are in the Cubilin (CUBN) gene.
Krahe, along with Maria Aminoff, a doctoral student from the University of Helsinki and visiting scientist at Ohio State, and Albert de la Chapelle, director of the Human Cancer Genetics Program at Ohio State, all believe that there is a third Finnish mutation -- FM3 -- waiting to be discovered.
This work on the genetic cause of megaloblastic anemia 1 was helped by the fact that it is more prevalent in Finland. Historically, the Finnish population has been isolated by geographic borders, Aminoff said. This confined these genetic mutations within a tight group of people.
At the same time, extensive medical and genealogical records are maintained by the Finnish government, and detailed marriage records are maintained by the church in that country. Together, these provide excellent tools for tracing the origin and spread of the gene mutations through the populations, she said. Krahe and his colleagues estimate the gene mutations began to spread as early as 1,000 to 1,300 years ago.
Along with the two identified Finnish mutations and the one thats as yet undiscovered, the researchers believe that two other mutations in Norwegian patients may be linked to the disease and at least one mutation from the Bedouin family.
Thats a total of six mutations in three distinct populations, Krahe said.
Researchers from the University of Helsinki, the Minerva Foundation Institute for Medical Research in Helsinki, the National Guard King Khalid Hospital in Saudi Arabia, Vestfold Central Hospital in Norway, University of Aarhus in Denmark, and the Hospital Tenon in Paris participated in the study. Funding was provided by the Ulla Hjelt Fund, Liv och Halsa, the Academy of Finland and the National Cancer Institute.