Genetics

DETERMINING CAUSES: Louis Kunkel believes that researching sarcoglycans will provide a better understanding of muscular dystrophy. C.G. Bonnemann, R. Modi, S. Noguchi, Y. Mizuno, M. Yoshida, E. Gussoni, E.M. McNally, D.J. Duggan, C. Angelini, E.P. Hoffman, E. Ozawa, L. Kunkel, "b-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex," Nature Genetics, 11:266-73, 1995. (Cited in 76 papers through August 1997) Comments by Louis M. Kunkel, Departments of Genetics and Pediatrics and Howard Hughes Medical Institute, Harvard Medical School L.E. Lim, F. Duclos, O. Broux, N. Bourg, Y. Sunada, V. Allamand, J. Meyer, I. Richard, C. Moomaw, C. Slaughter, F.M.S. Tome, M. Fardeau, C.E. Jackson, J.S. Beckmann, K.P. Campbell, "b-sarcoglycan: Characterization and role in limb-girdle muscular dystrophy linked to 4q12," Nature Genetics, 11:257-65, 1995. (Cited in 79 papers through August 1997) Comments by Kevin P. Campbell, Departments of Physiology, Biophysics, and Neurology and Howard Hughes Medical Institute, University of Iowa College of Medicine Dystrophin, a large, rodlike component of the membrane cytoskeleton of muscle fibers, is the protein product of the gene for severe muscular dystrophies. Over the years, dystrophin has been associated with a complex (known as the dystrophin-glycoprotein complex) of other proteins with which it functions. Called the sarcoglycans, these single transmembrane proteins have been isolated and cloned to determine their roles in the onset of muscular dystrophy. Louis M. Kunkel, a professor of pediatrics and genetics at Harvard Medical School and a Howard Hughes Medical Institute investigator, and Kevin P. Campbell, a professor of physiology, biophysics, and neurology at the University of Iowa and also a Howard Hughes Medical Institute investigator, each contributed to papers on b-sarcoglycan, one of the known components of the dystrophin complex. The two papers appeared simultaneously in a 1995 issue of Nature Genetics. "We still don't know what the sarcoglycans do," notes Kunkel. "But they are diminished in Duchenne dystrophy. So when dystrophin is absent, they go down, and when any one of them is absent, the whole complex virtually disappears. And so they are involved in something very important in the pathophysiology, which is still unknown." POSITIVE ID: Kevin Campbell's work with the Amish population of southern Indiana helped identify the mutation responsible for limb girdle muscular dystrophy. Both research teams cloned b-sarcoglycan, and mapped the protein to chromosome 4. While Kunkel's team based their study on a mutation of b-sarcoglycan found in a young girl suffering from muscular dystrophy, Campbell's lab focused on a small Amish population in southern Indiana. Because the members of the Amish population all marry within the community, individuals are often homozygotes for a mutation in b-sarcoglycan that results in an autosomal recessive form of dystrophy. "We found these families that had a limb girdle muscular dystrophy," explains Campbell. "We next identified a missense mutation [the alteration of one or more codons] in b- sarcoglycan and . . . demonstrated that this missense mutation perfectly cosegregates with all the affected individuals." Using an express sequence tag database, which contains small bits of sequenced DNA, Campbell's lab confirmed that the protein that they had isolated and cloned was indeed b- sarcoglycan. In their paper, Campbell's team also described a new screening assay for limb girdle muscular dystrophy called a touchdown polymerase chain reaction assay to identify the mutation. "It's a really nice, simple assay from a blood sample where we can identify whether the patient or an individual has this b-sarcoglycan missense mutation or not," he notes. "If you can identify carriers, as long as carriers don't marry other carriers, you can eliminate the disease." These families, many of whom include 11 or 13 children, commonly have five or six suffering from muscular dystrophy. Kunkel credits general interest in muscular dystrophy and in the sarcoglycan proteins for the popularity of both papers. "This class of proteins that's associated with dystrophin . . . were all previously unknown." Research on the sarcoglycans and the dystrophin complex will give scientists "a better understanding of the pathobiology of the disease-what's causing what you see physically," he maintains. Scientists will be able to better classify different types of dystrophy and, in doing so, will presumably be able to provide better counseling and treatment for patients. "We . . . now know that a particular dystrophy caused by a mutation in one of these things may respond to treatment quite differently than another," explains Kunkel. Both Campbell and Kunkel are currently researching an additional mutation of b-sarcoglycan found in patients. Campbell's work focuses on one family who has a second missense mutation in addition to the common mutation. Follow-up work from Kunkel has included studies on the role of other sarcoglycans such as a and g. "There's a burgeoning of literature of the mutations in patients," he adds. "And we're just starting to understand . . . the type of mutation and the cause it might have on the phenotype and on the complex."

Genetics

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