PXD012702

PXD012702 is an original dataset announced via ProteomeXchange.

Title	A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity
Description	We previously reported a pathogenic de novo W342 mutation in the transcriptional corepressor CtBP1 in four independent patients with neurodevelopmental disabilities. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CtBP1 mutation. Within this cohort we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia and tooth enamel defects present in all patients. The W342 mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cells lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.
HostingRepository	PRIDE
AnnounceDate	2019-05-09
AnnouncementXML	Submission_2019-05-09_00:16:37.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD012702
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Thirugnana Subramanian
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; Acetyl; Carbamidomethyl
Instrument	LTQ Orbitrap Velos; LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2019-02-14 02:02:08	ID requested
⏵ 1	2019-05-09 00:16:38	announced

Beck DB, Subramanian T, Vijayalingam S, Ezekiel UR, Donkervoort S, Yang ML, Dubbs HA, Ortiz-Gonzalez XR, Lakhani S, Segal D, Au M, Graham JM, Verma S, Waggoner D, Shinawi M, B, ö, nnemann CG, Chung WK, Chinnadurai G, A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity. Neurogenetics, 20(3):129-143(2019) [pubmed]

submitter keyword: Human, CtBP1, Proteomics

G. Chinnadurai
contact affiliation	Saint Louis University
contact email	chinnag@slu.edu
lab head
Thirugnana Subramanian
contact affiliation	St. Louis University
contact email	subramt@slu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD012702
     1. Label: PRIDE project
     2. Name: A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity