PXD039226

PXD039226 is an original dataset announced via ProteomeXchange.

Title	Insights into the role of a cardiomyopathy-causing genetic var-iant in ACTN2
Description	Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hyper-trophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 M228T variant were phenotyped by echocardiog-raphy. 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 M228T mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is em-bryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological ab-normalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormal-ities in sarcomeric parameters, cell cycle defects and mitochondrial dysfunction. The mutant al-pha-actinin protein is found to be destabilised, associated with increased activity of the ubiqui-tin-proteosomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteosomal system is activated; a mechanism which has been implicated in cardiomyopathies previously. In parallel, 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 death of the embryos. The defects also have wide-ranging morphological con-sequences.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:45:57.854.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sophie Broadway-Stringer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-03 07:25:48	ID requested
1	2023-05-10 09:02:13	announced
⏵ 2	2023-11-14 08:45:58	announced	2023-11-14: Updated project metadata.

Broadway-Stringer S, Jiang H, Wadmore K, Hooper C, Douglas G, Steeples V, Azad AJ, Singer E, Reyat JS, Galatik F, Ehler E, Bennett P, Kalisch-Smith JI, Sparrow DB, Davies B, Djinovic-Carugo K, Gautel M, Watkins H, Gehmlich K, . Cells, 12(5):(2023) [pubmed]

submitter keyword: embryonic heart, proteomics,alpha-actinin, sarcomere, mitochondria, cardiomyopathy

Katja Gehmlich
contact affiliation	The Institute of Cardiovascular Sciences College of Medical and Dental Sciences Institute of Biomedical Research (IBR) room 229 University of Birmingham Edgbaston, Birmingham, B15 2TT
contact email	k.gehmlich@bham.ac.uk
lab head
Sophie Broadway-Stringer
contact affiliation	University of Birmingham
contact email	s.a.broadway-stringer@bham.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD039226

PRIDE project URI

• PRIDE
  1. PXD039226
     1. Label: PRIDE project
     2. Name: Insights into the role of a cardiomyopathy-causing genetic var-iant in ACTN2