title: Prevalence of desmin mutations in dilated cardiomyopathy.
abstract: 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.
authors.affiliation: University of Colorado at Denver and Health Sciences Center, Denver, Colo, USA. Matthew.Taylor@UCHSC.edu
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.forename: Lisa
authors.initials: L
authors.lastname: Ku
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Elisa
authors.initials: E
authors.lastname: Carniel
authors.forename: Kurt
authors.initials: K
authors.lastname: Haubold
authors.forename: Mark M
authors.initials: MM
authors.lastname: Boucek
authors.forename: Debra
authors.initials: D
authors.lastname: Ferguson
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Graw
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Jean
authors.initials: J
authors.lastname: Cavanaugh
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.forename: Carlin S
authors.initials: CS
authors.lastname: Long
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
authors.forename: Philip
authors.initials: P
authors.lastname: Lavori
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
mesh_terms: 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
chemical_list: D003893:Desmin