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Background Familial cardiac myxomas occur in the hereditary syndrome Carney complex. Although PRKAR1A mutations can cause the Carney complex, the disorder is genetically heterogeneous. To identify the cause of a Carney complex variant associated with distal arthrogryposis (the trismus–pseudocamptodactyly syndrome), we performed clinical and genetic studies.
Methods A large family with familial cardiac myxomas and the trismus–pseudocamptodactyly syndrome (Family 1) was identified and clinically evaluated along with two families with trismus and pseudocamptodactyly. Genetic linkage analyses were performed with the use of microsatellite polymorphisms to determine a locus for this Carney complex variant. Positional cloning and mutational analyses of candidate genes were performed to identify the genetic cause of disease in the family with the Carney complex as well as in the families with the trismus–pseudocamptodactyly syndrome.
Results Clinical evaluations demonstrated that the Carney complex cosegregated with the trismus–pseudocamptodactyly syndrome in Family 1, and genetic analyses demonstrated linkage of the disease to chromosome 17p12–p13.1 (maximum multipoint lod score, 4.39). Sequence analysis revealed a missense mutation (Arg674Gln) in the perinatal myosin heavy-chain gene (MYH8). The same mutation was also found in the two families with the trismus–pseudocamptodactyly syndrome. Arg674 is highly conserved evolutionarily, localizes to the actin-binding domain of the perinatal myosin head, and is close to the ATP-binding site. We identified nonsynonymous MYH8 polymorphisms in patients with cardiac myxoma syndromes but without arthrogryposis.
Conclusions We describe a novel heart–hand syndrome involving familial cardiac myxomas and distal arthrogryposis and demonstrate that these disorders are caused by a founder mutation in the MYH8 gene. Our findings demonstrate novel roles for perinatal myosin in both the development of skeletal muscle and cardiac tumorigenesis.
Source Information
From the Molecular Cardiology Laboratory, Greenberg Cardiology Division, Departments of Medicine and Cell and Developmental Biology, Weill Medical College of Cornell University, New York (M.V., M.B., D.A.M., C.T.B.); the Departments of Pathology (S.W., C.C. Morton) and Obstetrics, Gynecology and Reproductive Biology (C.C. Morton), Brigham and Women's Hospital, Boston; the Division of Endocrinology and Metabolism, Department of Pediatrics, University of Kentucky College of Medicine, Lexington (C.C. Mabry); the Division of Plastic Surgery, Department of Surgery, University of South Carolina School of Medicine, Columbia (J.-F.L.); the Division of Cardiology, Evanston Northwestern Healthcare, Evanston, Ill. (A.Z.); the Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Loverval, Belgium (A.D.); and the Department of Cardiology, Jolimont Hospital, Jolimont, Belgium (J.-M.C.).
Address reprint requests to Dr. Basson at the Greenberg Cardiology Division, Dept. of Medicine, Weill Medical College of Cornell University, 525 E. 68th St., New York, NY 10021, or at ctbasson{at}med.cornell.edu.
Related Letters:
Mutation of Perinatal Myosin Heavy Chain
Stratakis C. A., Bertherat J., Carney J. A., Brown M. A., Morita H., Nagai R., Basson C. T., Veugelers M., McDermott D. A.
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N Engl J Med 2004;
351:2556-2558, Dec 9, 2004.
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