PXD044779

PXD044779 is an original dataset announced via ProteomeXchange.

Title	Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for correct mRNA splicing and ectodermal differentiation
Description	The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene-expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.
HostingRepository	PRIDE
AnnounceDate	2023-08-25
AnnouncementXML	Submission_2023-08-25_00:28:35.813.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	JeroenDemmers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-23 01:52:08	ID requested
⏵ 1	2023-08-25 00:28:36	announced

Dataset with its publication pending

submitter keyword: splicing factor,MPLKIP, TTD

JeroenDemmers
contact affiliation	Proteomics Center, Erasmus MC
contact email	j.demmers@erasmusmc.nl
lab head
JeroenDemmers
contact affiliation	Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands
contact email	j.demmers@erasmusmc.nl
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/2023/08/PXD044779

PRIDE project URI

• PRIDE
  1. PXD044779
     1. Label: PRIDE project
     2. Name: Trichothiodystrophy-associated MPLKIP maintains DBR1 levels for correct mRNA splicing and ectodermal differentiation