title: OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.
abstract: BACKGROUND
  Studies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes.
  
  
  RESULTS
  We identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample had two OBSCN mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with OBSCN mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control level).Obscurin levels in DCM controls, donor heart and myectomy samples were the same.
  
  
  CONCLUSIONS
  OBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations.
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Marston
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: Cecile
authors.initials: C
authors.lastname: Montgiraud
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Munster
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: O'Neal
authors.initials: O
authors.lastname: Copeland
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: Onjee
authors.initials: O
authors.lastname: Choi
authors.affiliation: Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Dos Remedios
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Messer
authors.affiliation: Randall Division, King's College London, London, United Kingdom.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ehler
authors.affiliation: NHLI, Imperial College London, London, United Kingdom.
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
mesh_terms: D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D064067:Rho Guanine Nucleotide Exchange Factors; C578224:OBSCN protein, human; D017346:Protein Serine-Threonine Kinases