Investigators have developed lab mice likely to advance understanding of the fukutin-deficient disorders Fukuyama congenital muscular dystrophy and type 2M limb-girdle muscular dystrophy
By disrupting the fukutin gene at different time points in mice embryo, researchers have been able to develop research models of two types of human muscle disease: Fukuyama congenital muscular dystrophy (Fukuyama CMD) and type 2M limb-girdle muscular dystrophy (LGMD2M).
Both types of muscular dystrophy are caused by deficiencies of the fukutin protein, resulting from mutations in both copies of the fukutin gene.
Until now, researchers have not been able to create a fukutin-deficient mouse that reflects the kinds of muscle abnormalities seen in people with muscular dystrophy.
MDA grantee Aaron Beedle at the University of Georgia and colleagues, including longtime MDA grantee Kevin Campbell at the University of Iowa, conducted the mouse experiments, publishing their findings Sept. 4, 2012, in the Journal of Clinical Investigation. (Beedle was in the laboratory of Kevin Campbell at Iowa when most of this work was done.)
In research mice, when fukutin is completely absent from the earliest stages of embryonic development, the embryo does not survive, which has complicated the development of a fukutin-deficient mouse for laboratory experiments.
In the current study, investigators disrupted the fukutin gene in the muscle tissue of mouse embryos on the eighth or the 17th day of development.
Both embryonic disruptions allowed the experimental mice to be born alive, but with prominent muscle defects characteristic of the diseases.
The mice in which the fukutin gene was disrupted on embryonic day 8 fared worse than those with disruption on day 17, supporting evidence that fukutin plays an important role in early muscle development.
Beedle and colleagues say this conditional knockout mouse — a mouse in which researchers can control when and in what tissues a gene is turned on and off — will allow scientists to conduct better studies of fukutin's role in muscle tissue and to analyze what happens when this protein is absent.
It’s known that an important role of fukutin in muscle cells is to assist with "sugar coating" (glycosylation) of a protein that's attached to the surface of muscle fibers and in turn connects the fibers to material outside them.
Without fukutin, sugar coating of this surface-associated protein is deficient, and the protein — alpha-dystroglycan — fails to play its "gluelike" role in connecting muscle fibers to the surrounding area.
Fukuyama CMD is most common in people of Japanese descent and is caused by a specific mutation on both copies of the fukutin gene. (Humans have two copies of most genes in each cell.) Other types of muscular dystrophy can sometimes result from fukutin mutations as well.
LGMD2M is less common; is found in people of Japanese descent and other ethnic backgrounds; and is typically caused by mutations in the fukutin gene that cause a smaller disruption of fukutin activity than those that cause CMD.
Fukuyama CMD symptoms begin during the first year of life and are characterized by lack of muscle tone, weakness of the face and limb muscles, and adverse effects on the brain. Children often do not survive to adulthood.
LGMD2M has a later onset, with poor muscle tone and delayed motor milestones. It's generally a milder disorder than Fukuyama MD. Weakness is greater in the legs than arms,and in the muscles closer to the center of the body than the muscles distant from the center.
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