PXD035393

PXD035393 is an original dataset announced via ProteomeXchange.

Title	Minimal expression of dysferlin prevents development of muscular dystrophy in dysferlin exon 40a knockout mice
Description	Dysferlin is an essential muscle membrane repair protein and autosomal recessive mutations in its gene result in progressive muscular dystrophies collectively called dysferlinopathies. We previously showed that calpain-mediated cleavage within dysferlin exon 40a releases a 72kDa C-terminal minidysferlin recruited to injured sarcolemma. In the current study, we hypothesised that knocking out exon 40a will lead to defective membrane repair and development of muscular dystrophy over time. To address this hypothesis, we created three exon 40a knockout (40aKO) mouse lines with dysferlin protein levels ranging from ~80% of wildtype (WT) in 40aKO-3, ~50% in 40aKO-2 and ~10-20% in 40aKO-1 mice. Histopathological analysis of skeletal muscles harvested from all 12-month-old 40aKO mice showed little evidence of dystrophic features seen in dysferlin-null BLAJ mice. Lipidomics analysis on 18wk old quadriceps showed that all 40aKO lines had a similar lipidomic profile to WT and distinct from BLAJs. The proteomic profile of 40aKO lines was intermediate between that of WT and BLAJs. Laser membrane damage assays showed normal membrane repair capacity in all three 40aKO lines. These results collectively indicate that ~10-20% of dysferlin protein expression is sufficient for maintenance of the lipidome and membrane repair capacity, and crucially prevents development of muscular dystrophy.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:41:31.867.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD035393
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Chi Nam Ignatius Pang
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-20 00:09:30	ID requested
1	2023-03-11 03:11:56	announced
⏵ 2	2023-11-14 08:41:32	announced	2023-11-14: Updated project metadata.

10.6019/PXD035393;

Yasa J, Reed CE, Bournazos AM, Evesson FJ, Pang I, Graham ME, Wark JR, Nijagal B, Kwan KH, Kwiatkowski T, Jung R, Weisleder N, Cooper ST, Lemckert FA, Minimal expression of dysferlin prevents development of dysferlinopathy in dysferlin exon 40a knockout mice. Acta Neuropathol Commun, 11(1):15(2023) [pubmed]

submitter keyword: muscular dystrophy, exon knockout, mice, dysferlin

Chi Nam Ignatius Pang
contact affiliation	Children's Medical Research Institute, Westmead, Sydney, Australia
contact email	ipang@cmri.org.au
lab head
Chi Nam Ignatius Pang
contact affiliation	Children's Medical Research Insitute
contact email	ipang@cmri.org.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035393
     1. Label: PRIDE project
     2. Name: Minimal expression of dysferlin prevents development of muscular dystrophy in dysferlin exon 40a knockout mice