PXD018013

PXD018013 is an original dataset announced via ProteomeXchange.

Title	NAA15 haploinsufficiency can cause congenital heart disease and perturbs protein levels in induced pluripotent stem cells
Description	NAA15 is a component of the NatA complex that acetylates amino terminal (Nt) protein residues and influences protein synthesis. We identified multiple damaging NAA15 variants in congenital heart disease patients, including four loss-of-function (LoF) variants, one missense (R276W) de novo variant and 15 rare inherited missense variants. To understand the effects of these variants on NatA complex activity, we introduced heterozygous LoF, compound heterozygous and missense residues iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to alterations in the amount and composition of the NatA complex. Mass spectrometry (MS)-based N-terminomics analyses showed that nearly 80% of iPS cell proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells, 32 and 9 NatA-specific targeted proteins differed in their Nt-acetylation degree, respectively. In addition, the steady-state protein levels of more than 560 proteins were altered in mutant compared to wild type cells. While most NatA-specific Nt-acetylated proteins were fully acetylated, ~19 proteins were partially acetylated. NAA15-haploinsufficiency abrogated Nt-acetylation of 4 of these proteins but did not affect the acetylation of the other 15 proteins. Similar patterns of acetylation loss in few proteins were observed in both NAA15 haploinsufficient and NAA15 R276W iPS cells. These studies define human proteins that appear to require the full NAA15 complex for normal acetylation and imply that deficiencies in one or more of these NAA15 target proteins contribute to normal cardiac development. The current dataset contains all N-terminomics data related to this study.
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_10:37:29.247.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD018013
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	An Staes
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-12 03:18:02	ID requested
⏵ 1	2024-10-07 10:37:30	announced

10.1161/circresaha.120.316966;

Ward T, Tai W, Morton S, Impens F, Van Damme P, Van Haver D, Timmerman E, Venturini G, Zhang K, Jang MY, Willcox JAL, Haghighi A, Gelb BD, Chung WK, Goldmuntz E, Porter GA, Lifton RP, Brueckner M, Yost HJ, Bruneau BG, Gorham J, Kim Y, Pereira A, Homsy J, Benson CC, DePalma SR, Varland S, Chen CS, Arnesen T, Gevaert K, Seidman C, Seidman JG, Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency. Circ Res, 128(8):1156-1169(2021) [pubmed]

10.6019/PXD018013;

submitter keyword: iPSC,N-terminal acetylation, N-terminomics

Jonathan Seidman
contact affiliation	1 Department of Genetics, Harvard Medical School, Boston, MA 02115
contact email	seidman@genetics.med.harvard.edu
lab head
An Staes
contact affiliation	Medical Protein Chemistry
contact email	an.staes@vib-ugent.be
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/2021/08/PXD018013

PRIDE project URI

• PRIDE
  1. PXD018013
     1. Label: PRIDE project
     2. Name: NAA15 haploinsufficiency can cause congenital heart disease and perturbs protein levels in induced pluripotent stem cells