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(Circulation. 2007;115:1244-1251.)
© 2007 American Heart Association, Inc.

Genetics

Prevalence of Desmin Mutations in Dilated Cardiomyopathy

Matthew R.G. Taylor, MD, PhD; Dobromir Slavov, PhD; Lisa Ku, MS; Andrea Di Lenarda, MD; Gianfranco Sinagra, MD; Elisa Carniel, MD; Kurt Haubold, PhD; Mark M. Boucek, MD; Debra Ferguson, RN, MS; Sharon L. Graw, PhD; Xiao Zhu, BS; Jean Cavanaugh, MS, PA-C; Carmen C. Sucharov, PhD; Carlin S. Long, MD; Michael R. Bristow, MD, PhD; Philip Lavori, PhD; Luisa Mestroni, MD, for the Familial Cardiomyopathy Registry and the BEST (Beta-Blocker Evaluation of Survival Trial) DNA Bank

From the University of Colorado at Denver and Health Sciences Center, Denver, Colo (M.R.G.T., D.S., L.K., E.C., K.H., D.F., S.L.G., X.Z., C.C.S., C.S.L., M.R.B., L.M.); Department of Cardiology, University Hospital, Trieste, Italy (A.D.L., G.S.); Division of Cardiology, The Children’s Hospital, Denver, Colo (M.M.B., J.C.); and Stanford University and the Cooperative Studies Program, Department of Veterans Affairs, Stanford, Calif (P.L.).

Reprint requests to Matthew Taylor, MD, PhD, 12635 E Montview Blvd, Suite 150, Aurora, CO 80010-7116. E-mail Matthew.Taylor{at}UCHSC.edu

Received June 16, 2006; accepted December 29, 2006.

Background— Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known.

Methods and Results— Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects.

Conclusions— The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.

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