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  • Jiang, HeUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)

Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant

  • Artikel/kapitelEngelska2021

Förlag, utgivningsår, omfång ...

  • 2021-02-26
  • Springer,2021
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-439921
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-439921URI
  • https://doi.org/10.1007/s00395-021-00853-zDOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Titin truncating variants are a well-established cause of cardiomyopathy; however, the role of titin missense variants is less well understood. Here we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported titin A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Heterozygous and homozygous mice carrying the titin A178D missense variant were characterised in vivo by echocardiography. Heterozygous mice had no detectable phenotype at any time point investigated (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the foetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified downregulation of telethonin and four-and-a-half LIM domain 2, as well as the upregulation of heat shock proteins and myeloid leukaemia factor 1. Loss of telethonin from the cardiac Z-disc was accompanied by proteasomal degradation; however, unfolded telethonin accumulated in the cytoplasm, leading to a proteo-toxic response in the mice.We show that the titin A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism: because the titin A178D variant abolishes binding of telethonin, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of telethonin by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Hooper, CharlotteUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Kelly, MatthewUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Steeples, ViolettaUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Simon, Jillian N.Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Beglov, JuliaUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Azad, Amar J.Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Leinhos, LisaUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Bennett, PaulineKings Coll London, BHF Ctr Res Excellence, Sch Cardiovasc Med & Sci, Randall Ctr Cell & Mol Biophys, London, England. (författare)
  • Ehler, ElisabethKings Coll London, BHF Ctr Res Excellence, Sch Cardiovasc Med & Sci, Randall Ctr Cell & Mol Biophys, London, England. (författare)
  • Kalisch-Smith, Jacinta, IUniv Oxford, Dept Physiol Anat & Genet, Oxford, England. (författare)
  • Sparrow, Duncan B.Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. (författare)
  • Fischer, RomanUniv Oxford, Target Discovery Inst, Nuffield Dept Clin Med, Oxford, England. (författare)
  • Heilig, RaphaelUniv Oxford, Target Discovery Inst, Nuffield Dept Clin Med, Oxford, England. (författare)
  • Isackson, HenrikUppsala universitet,Kardiologi,Integrativ Fysiologi(Swepub:uu)henis210 (författare)
  • Ehsan, MehrozUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Patone, GianninoMax Delbrueck Ctr Mol Med, Berlin, Germany. (författare)
  • Huebner, NorbertMax Delbrueck Ctr Mol Med, Berlin, Germany. (författare)
  • Davies, BenjaminUniv Oxford, Wellcome Ctr Human Genet, Transgen Core, Oxford, England. (författare)
  • Watkins, HughUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England. (författare)
  • Gehmlich, KatjaUniv Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England.;Univ Birmingham, Inst Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England. (författare)
  • Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford OX3 9DU, England.;Univ Oxford, British Heart Fdn Ctr Res Excellence Oxford, Oxford OX3 9DU, England.Kings Coll London, BHF Ctr Res Excellence, Sch Cardiovasc Med & Sci, Randall Ctr Cell & Mol Biophys, London, England. (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Basic Research in Cardiology: Springer1160300-84281435-1803

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