PXD017530

PXD017530 is an original dataset announced via ProteomeXchange.

Title	Intronic CRISPR repair in LZTR1-deficient iPSC-cardiomyocytes from Noonan syndrome patients reveals new treatment options
Description	Noonan syndrome (NS) is a multisystemic developmental disorder characterized by its clinical variability with common symptoms such as typical facial dysmorphism, short stature, developmental delay and intellectual disability as well as congenital heart disease. The disease is causally linked to gain-of-function mutations in a number of genes leading to an increased signal transduction along the RAS-MAP kinase (MAPK) signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. In this study, we present a family with two siblings displaying an autosomal recessive form of NS with severe hypertrophic cardiomyopathy caused by biallelic mutations within leucine zipper like transcription regulator 1 (LZTR1). Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of the affected siblings recapitulated the hypertrophic phenotype and uncovered a causal link between LZTR1 dysfunction, RAS accumulation, RAS-MAPK signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Intronic CRISPR repair in the patients’ iPSCs normalized RAS-MAPK signaling activity and cellular hypertrophy paving the way for personalized medical treatment.
HostingRepository	PRIDE
AnnounceDate	2020-08-25
AnnouncementXML	Submission_2020-08-25_07:20:36.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christof Lenz
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-16 23:29:09	ID requested
⏵ 1	2020-08-25 07:20:37	announced

Hanses U, Kleinsorge M, Roos L, Yigit G, Li Y, Barbarics B, El-Battrawy I, Lan H, Tiburcy M, Hindmarsh R, Lenz C, Salinas G, Diecke S, M, ü, ller C, Adham I, Altm, ü, ller J, N, ü, rnberg P, Paul T, Zimmermann WH, Hasenfuss G, Wollnik B, Cyganek L, Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy. Circulation, 142(11):1059-1076(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: iPSC, stem cell, SILAC, proteomics

Christof Lenz
contact affiliation	University Medical Center Goettingen, Institute of Clinical Chemistry, Core Facility Proteomics
contact email	christof.lenz@mpibpc.mpg.de
lab head
Christof Lenz
contact affiliation	Max Planck Institute for Biophysical Chemistry
contact email	christof.lenz@mpibpc.mpg.de
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/2020/08/PXD017530

PRIDE project URI

• PRIDE
  1. PXD017530
     1. Label: PRIDE project
     2. Name: Intronic CRISPR repair in LZTR1-deficient iPSC-cardiomyocytes from Noonan syndrome patients reveals new treatment options