BioWorld International Correspondent

A search for the gene or genes responsible for the autoimmune disease myasthenia gravis has been narrowed down to a small segment of chromosome 6. The French researchers who carried out the study believe that they soon will find the gene linked to that disease, as well as genes for other autoimmune conditions.

Henri-Jean Garchon, director of research at the Institut National de la Sante et de la Recherche Medicale in Paris, told BioWorld International: "We think that the causative gene is in there. We plan to carry out sequencing to identify the variants that are responsible for the disease association, and we think there is a good chance that we will also pinpoint genes involved in other autoimmune diseases, such as rheumatoid arthritis and autoimmune thyroid disease."

Garchon, together with collaborators at other institutions in Paris, reported his findings in a paper in the Oct. 11, 2004, issue of Proceedings of the National Academy of Sciences. The paper is titled "Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia."

Myasthenia gravis affects about one in 10,000 people. It mainly affects females, with the age of onset ranging between 20 and 40. It results when the thymus begins to manufacture auto-antibodies, which attack the acetylcholine receptor on the neuromuscular junction, thus blocking the onward transmission of the nerve impulse.

The result is fatigue, particularly following exercise, but the disease also can be fatal if it affects the respiratory muscles.

Earlier research had shown that the gene for myasthenia gravis was associated with the human leukocyte antigen (HLA) complex on chromosome 6, but its exact identity remained unknown.

The HLA complex is a large region of the genome, comprising 3.5 Mb. Its sequence, completed four years ago, showed that it has about 220 genes within it, making it the richest part of the genome.

That region includes the genes that encode the Class I and Class II HLAs, which have proteins responsible for presentation of antigens to cells of the immune system, thus triggering the cellular and humoral immune responses. Recently, studies have shown that many other genes in the HLA region, outside of the Class I and II genes, also play key roles in modulating the immune system. Those include genes coding for the cytokine tumor necrosis factor and the complement proteins.

Within the HLA complex, Garchon and his group focused on the 8.1 ancestral haplotype - a stretch of the genome normally inherited in one piece. Scientists knew that the MYAS1 locus was in that haplotype, but because it contains many different genes, it was difficult to identify which one was associated with MYAS1.

As well as being prone to myasthenia gravis, people with the 8.1 haplotype are more likely to develop a host of other autoimmune diseases, including rheumatoid arthritis, autoimmune thyroiditis, Type I diabetes, celiac disease and systemic lupus.

As the PNAS paper reported, Garchon and his team compared the inheritance of closely spaced markers within the region of the 8.1 haplotype by French Caucasian individuals with myasthenia gravis and their parents, with inheritance of the same markers by a group of unrelated controls.

"This approach allowed us to pinpoint the smallest segments of chromosomes that were necessary for predisposition to the disease," Garchon explained.

As well as narrowing down the location of MYAS1, they were able to confirm, for the first time, that MYAS1 was outside the groups of Class I and II HLA genes.

Garchon's group also measured the levels of auto-antibodies in the serum of patients with myasthenia gravis, and correlated the levels with the patients' genotypes. Their experiments allowed them to identify genes involved in controlling the production of the auto-antibodies, including some that suppress their production.

"This information, although basic at the moment, will be important to allow scientists to understand the mechanisms that regulate the production of antibodies, especially in response to vaccines," Garchon said. The discovery fits in well with pre-existing knowledge that haplotype 8.1 includes a locus that confers low antibody response to hepatitis B vaccine, he added.

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