Prevalence of desmin mutations in dilated cardiomyopathy.
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.


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.
Taylor
Matthew R G
MR
University of Colorado at Denver and Health Sciences Center, Denver, Colo, USA. Matthew.Taylor@UCHSC.edu
Slavov
Dobromir
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Ku
Lisa
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Di Lenarda
Andrea
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Sinagra
Gianfranco
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Carniel
Elisa
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Haubold
Kurt
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Boucek
Mark M
MM
Ferguson
Debra
D
Graw
Sharon L
SL
Zhu
Xiao
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Cavanaugh
Jean
J
Sucharov
Carmen C
CC
Long
Carlin S
CS
Bristow
Michael R
MR
Lavori
Philip
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Mestroni
Luisa
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D000328:Adult; D000368:Aged; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D002478:Cells, Cultured; D015331:Cohort Studies; D003893:Desmin / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015995:Prevalence; D051381:Rats; D012042:Registries; D014162:Transfection; D014481:United States / Q000453:epidemiology
D003893:Desmin