-
Je něco špatně v tomto záznamu ?
Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2
S. Broadway-Stringer, H. Jiang, K. Wadmore, C. Hooper, G. Douglas, V. Steeples, AJ. Azad, E. Singer, JS. Reyat, F. Galatik, E. Ehler, P. Bennett, JI. Kalisch-Smith, DB. Sparrow, B. Davies, K. Djinovic-Carugo, M. Gautel, H. Watkins, K. Gehmlich
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
Wellcome Trust - United Kingdom
British Heart Foundation - United Kingdom
Free Medical Journals od 2012
PubMed Central od 2012
Europe PubMed Central od 2012
ProQuest Central od 2012-03-01
Open Access Digital Library od 2012-01-01
Open Access Digital Library od 2012-01-01
ROAD: Directory of Open Access Scholarly Resources od 2012
Odkazy
PubMed
36899856
DOI
10.3390/cells12050721
Knihovny.cz E-zdroje
- MeSH
- aktinin metabolismus MeSH
- hypertrofická kardiomyopatie * MeSH
- kardiomyopatie * MeSH
- myši MeSH
- srdce MeSH
- ubikvitiny MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hypertrophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocardiography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell-cycle defects and mitochondrial dysfunction. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteasomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteasomal system is activated; a mechanism that has been implicated in cardiomyopathies previously. In parallel, a lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell-cycle defects, the likely cause of the death of the embryos. The defects also have wide-ranging morphological consequences.
Department of Physiology Anatomy and Genetics University of Oxford Oxford OX1 3PT UK
Department of Physiology Faculty of Science Charles University 12800 Prague Czech Republic
European Molecular Biology Laboratory 38000 Grenoble France
Institute of Cardiovascular Sciences University of Birmingham Birmingham B15 2TT UK
Randall Centre for Cell and Molecular Biophysics King's College London London SE1 9RT UK
Transgenic Core Wellcome Centre for Human Genetics University of Oxford Oxford OX3 7BN UK
- 000
- 00000naa a2200000 a 4500
- 001
- bmc23004109
- 003
- CZ-PrNML
- 005
- 20230425141111.0
- 007
- ta
- 008
- 230418s2023 sz f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.3390/cells12050721 $2 doi
- 035 __
- $a (PubMed)36899856
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a sz
- 100 1_
- $a Broadway-Stringer, Sophie $u Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
- 245 10
- $a Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2 / $c S. Broadway-Stringer, H. Jiang, K. Wadmore, C. Hooper, G. Douglas, V. Steeples, AJ. Azad, E. Singer, JS. Reyat, F. Galatik, E. Ehler, P. Bennett, JI. Kalisch-Smith, DB. Sparrow, B. Davies, K. Djinovic-Carugo, M. Gautel, H. Watkins, K. Gehmlich
- 520 9_
- $a Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hypertrophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocardiography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell-cycle defects and mitochondrial dysfunction. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteasomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteasomal system is activated; a mechanism that has been implicated in cardiomyopathies previously. In parallel, a lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell-cycle defects, the likely cause of the death of the embryos. The defects also have wide-ranging morphological consequences.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a aktinin $x metabolismus $7 D000185
- 650 12
- $a kardiomyopatie $7 D009202
- 650 12
- $a hypertrofická kardiomyopatie $7 D002312
- 650 _2
- $a srdce $7 D006321
- 650 _2
- $a ubikvitiny $7 D014452
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Jiang, He $u Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK
- 700 1_
- $a Wadmore, Kirsty $u Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
- 700 1_
- $a Hooper, Charlotte $u Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK
- 700 1_
- $a Douglas, Gillian $u Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK $1 https://orcid.org/0000000290905326
- 700 1_
- $a Steeples, Violetta $u Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK
- 700 1_
- $a Azad, Amar J $u Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK $1 https://orcid.org/0000000314727668
- 700 1_
- $a Singer, Evie $u Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
- 700 1_
- $a Reyat, Jasmeet S $u Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK $1 https://orcid.org/0000000332479186
- 700 1_
- $a Galatik, Frantisek $u Department of Physiology, Faculty of Science, Charles University, 12800 Prague, Czech Republic $1 https://orcid.org/0000000281752604
- 700 1_
- $a Ehler, Elisabeth $u Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 9RT, UK $u School of Cardiovascular and Metabolic Medicine and Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London SE1 9RT, UK $1 https://orcid.org/0000000156465964
- 700 1_
- $a Bennett, Pauline $u Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 9RT, UK
- 700 1_
- $a Kalisch-Smith, Jacinta I $u Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
- 700 1_
- $a Sparrow, Duncan B $u Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK $1 https://orcid.org/0000000211416613
- 700 1_
- $a Davies, Benjamin $u Transgenic Core, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
- 700 1_
- $a Djinovic-Carugo, Kristina $u European Molecular Biology Laboratory, 38000 Grenoble, France $u Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, 1030 Vienna, Austria $1 https://orcid.org/0000000302522972
- 700 1_
- $a Gautel, Mathias $u School of Basic and Medical Biosciences, British Heart Foundation Centre of Research Excellence, King's College London, London SE1 9RT, UK
- 700 1_
- $a Watkins, Hugh $u Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK
- 700 1_
- $a Gehmlich, Katja $u Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK $u Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK $1 https://orcid.org/0000000340191844
- 773 0_
- $w MED00194911 $t Cells $x 2073-4409 $g Roč. 12, č. 5 (2023)
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/36899856 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20230418 $b ABA008
- 991 __
- $a 20230425141108 $b ABA008
- 999 __
- $a ok $b bmc $g 1924648 $s 1190318
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2023 $b 12 $c 5 $e 20230224 $i 2073-4409 $m Cells $n Cells $x MED00194911
- GRA __
- $p Wellcome Trust $2 United Kingdom
- GRA __
- $p British Heart Foundation $2 United Kingdom
- LZP __
- $a Pubmed-20230418