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

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

Jiang, He (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.

Hooper, Charlotte (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.

Kelly, Matthew (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.

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Steeples, Violetta (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.

Simon, Jillian N. (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.

Beglov, Julia (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.

Azad, Amar J. (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.

Leinhos, Lisa (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.

Bennett, Pauline (författare): Kings Coll London, BHF Ctr Res Excellence, Sch Cardiovasc Med & Sci, Randall Ctr Cell & Mol Biophys, London, England.

Ehler, Elisabeth (författare): Kings Coll London, BHF Ctr Res Excellence, Sch Cardiovasc Med & Sci, Randall Ctr Cell & Mol Biophys, London, England.

Kalisch-Smith, Jacinta, I (författare): Univ Oxford, Dept Physiol Anat & Genet, Oxford, England.

Sparrow, Duncan B. (författare): Univ Oxford, Dept Physiol Anat & Genet, Oxford, England.

Fischer, Roman (författare): Univ Oxford, Target Discovery Inst, Nuffield Dept Clin Med, Oxford, England.

Heilig, Raphael (författare): Univ Oxford, Target Discovery Inst, Nuffield Dept Clin Med, Oxford, England.

Isackson, Henrik (författare): Uppsala universitet,Kardiologi,Integrativ Fysiologi

Ehsan, Mehroz (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.

Patone, Giannino (författare): Max Delbrueck Ctr Mol Med, Berlin, Germany.

Huebner, Norbert (författare): Max Delbrueck Ctr Mol Med, Berlin, Germany.

Davies, Benjamin (författare): Univ Oxford, Wellcome Ctr Human Genet, Transgen Core, Oxford, England.

Watkins, Hugh (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.

Gehmlich, Katja (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.;Univ Birmingham, Inst Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England.

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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)

2021-02-26
2021
Engelska.
Ingår i: Basic Research in Cardiology. - : Springer. - 0300-8428 .- 1435-1803. ; 116

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://uu.diva-port... (primary) (Raw object); https://link.springe...; https://urn.kb.se/re...; https://doi.org/10.1...; visa färre...

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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.

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

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