Mutation Causes Muscular Dystrophy With Cognitive Impairment

Emma Hitt, PhD

March 10, 2011

March 10, 2011 — Researchers have provided the first genetic evidence to indicate that the dystroglycan-encoding gene (DAG1) is directly involved in the development of limb-girdle muscular dystrophy with associated cognitive dysfunction.

Kevin P. Campbell, PhD, with the University of Iowa in Iowa City, and colleagues have for the first time identified a dystroglycan missense mutation, T192M, in a patient with mild limb-girdle muscular dystrophy and cognitive impairment.

"We show that the missense mutation specifically causes hypoglycosylation of α-dystroglycan and a consequent loss of laminin binding," Dr. Campbell told Medscape Medical News.

Despite extensive efforts, he said, "no mutation has been identified in the dystroglycan gene, and it remains unclear whether dystroglycan is the sole substrate of these enzymes or if other substrates contribute to the pathogenesis of these diseases."

Dr. Campbell and colleagues report the findings in the March 10 issue of the New England Journal of Medicine.

A Genetic Basis for Cognitive Impairment

To establish an association between the dystroglycan gene and cognitive impairment, the researchers used a knock-in mouse model harboring the same mutation and demonstrated similar immunohistochemical and neuromuscular abnormalities as those observed in the woman with limb-girdle muscular dystrophy and cognitive impairment.

According to the researchers, α-dystroglycan is modified in the mucin domain with O-linked oligosaccharides that are "essential for its normal function as an extracellular-matrix receptor in various tissues, including skeletal muscle and brain."

Dr. Campbell noted that a deficiency in the glycosylation of dystroglycan has been linked to approximately 50% of diseases that are collectively referred to as secondary dystroglycanopathies; these disorders often feature brain abnormalities, although the symptoms of muscular dystrophy may be mild or may even go undiagnosed.

"Taken together, our studies reveal that the T192M patient and the knock-in mouse model recapitulate the biochemical and pathological phenotypes of patients with dystroglycanopathies, even though all the glycosyltransferases are normally expressed," Dr. Campbell said.

"Thus, our data provide direct genetic evidence that dystroglycan is the main, and most likely the only, molecule that bears O-linked glycans whose abnormalities cause muscular dystrophy with brain abnormalities."

Novel Therapeutic Targets

Asked to comment on these findings, Carsten G. Bönnemann, MD, with the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, said the study findings are significant and provide "compelling human genetic evidence for the central role and importance of α-dystroglycan’s function as a matrix receptor in this group of muscular dystrophies."

The study demonstrates that a primary mutation in α-dystroglycan that is also associated with the cognitive impairment phenotype "is the dysfunction of α-dystroglycan itself (without having to invoke additional players) and is responsible for the cognitive phenotype," he told Medscape Medical News.

According to Dr. Bönnemann, finding ways to improve the specific glycosylation responsible for α-dystroglycan’s binding to the matrix (the LARGE-dependent glycoepitope) would be a bona-fide therapeutic strategy. "The current finding would strongly support this approach," he said.

Another implication, said Dr. Bönnemann, is that genetic analysis of α-dystroglycan itself now has to be added to the diagnostic repertoire for the workup of a patient with an α-dystroglycanopathy of unknown type.

However, he pointed out, primary mutations in α-dystroglycan "likely are a rare cause, so that other α-dystroglycan–modifying genes remain to be discovered to explain the remainder of patients with evidence for an α-dystroglycanopathy."

The study was supported in part by grants to various investigators from the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, the Hacettepe University Research Fund, the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Muscular Dystrophy Campaign and Institute of Child Health Biomedical Research Center. Dr. Campbell is an investigator at the Howard Hughes Medical Institute. The study authors have disclosed no relevant financial relationships.

N Engl J Med. 2011;364:939-946.

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