U. IOWA (US) — Scientists have identified a new gene mutation that causes a type of muscular dystrophy that manifests itself in cognitive ways, not muscular ones.
The discovery has led to the creation of a mouse model to screen potential therapy drugs for the inherited disorder.
The research, published in the New England Journal of Medicine, ties together almost two decades of research on dystroglycan, an important muscle protein that is abnormal in a group of congenital muscular dystrophies, often involving brain abnormalities.
Normal dystroglycan protein is extensively modified with added sugar chains, allowing it to interact with other cellular proteins to provide structural strength and integrity to cell membranes in a variety of tissues, including muscle and the brain.
Several enzymes are involved in adding sugar chains onto the dystroglycan protein, and mutations in these enzymes cause congenital muscular dystrophies collectively known as secondary dystroglycanopathies.
In these disorders, too few sugar groups are added to the dystroglycan protein so it doesn’t attach properly to other proteins leading to muscle and neurological problems.
“In all these muscular dystrophies, the core dystroglycan protein is normal, so there was always the question of, ‘Did the sugar-adding enzymes act on other proteins as well as dystroglycan, and could those other unknown proteins be important for muscular dystrophy?'” says Kevin Campbell, professor of molecular physiology and biophysics and of internal medicine and neurology at the University of Iowa.
“Finding a mutation in the dystroglycan protein itself, which produces similar muscle and brain problems as are seen in these ‘secondary’ muscular dystrophies, suggests that dystroglycan is the major substrate, and probably the only substrate, in these other diseases.”
The international team of researchers collaborated to study the mutation found in a Turkish patient with a mild muscular dystrophy and severe cognitive impairment.
All the genes for the known sugar-adding enzymes were normal, but there was a single mutation in the gene for the dystroglycan protein. Further analysis showed that the mutated protein did not get its full complement of added sugar molecules, and was not able to interact efficiently with its normal cell partners either in muscle or brain.
The mutation blocked normal interaction between dystroglycan and one of the sugar-adding enzymes, thus disrupting the addition of sugar chains required for dystroglycan to function.
The genetic mutation was engineered into mouse dystroglycan. The animals have muscle and brain abnormalities similar to the Turkish patient and to patients with the secondary dystroglycanopathies.
Taken together, the data strongly suggests that the mutation causes neurological problems as well as muscle disease as a consequence of impaired dystroglycan modification.
“A particularly exciting aspect of this study is the new mouse that we have developed, which has the mutation in the dystroglycan protein,” Campbell says.
“It will give us a really good model to test therapies for their potential to boost the action of the sugar-adding enzymes and see if that helps reduce the severity of the muscle and neurological symptoms.”
The discovery of the mutation in the dystroglycan protein itself reveals an example of a new disease class known as primary dystroglycanopathy, Campbell says.
Although this finding is based on only one patient, the mutation produced such mild muscle disease, especially compared to the severe cognitive symptoms, that it was not immediately obvious that the patient had a muscular dystrophy.
“This might mean that there are other patients who have not been correctly diagnosed as having a muscular dystrophy because their major symptoms are cognitive rather than muscular,” Campbell says.
“Sometimes you just need that first patient case for clinicians to recognize that they have patients whose symptoms may also be caused by a particular mutation.”
The study was funded in part by the National Institutes of Health.
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