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PXD044186

PXD044186 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCiliopathy-associated missense mutations in IFT140 are hypomorphic and have edgetic effects on protein interaction networks
DescriptionThe mechanisms underlying recessive Mendelian diseases and the interplay between genotype and phenotype still need to be better understood. It is therefore necessary to characterise the functional effects of missense mutations at the protein level. Here we focus on missense mutations in the intraflagellar transport protein IFT140, which forms part of the IFT complex A (IFT-A), a crucial component of the ciliary machinery. Mutations in IFT140 can cause a vast spectrum of diseases belonging to the group of ciliopathies, reaching from isolated retinal dystrophy to severe skeletal abnormalities and multi-organ diseases such as Mainzer-Saldino and Jeune syndrome. We hypothesise that missense mutations in IFT140 are hypomorphic leading to quantitative effects on a subset of protein-protein interactions. This may affect complex stability as well as perturbations of protein interaction networks. In this work we assessed how 24 missense mutations in IFT140 affect interactions with other IFT and effector proteins using affinity purification coupled to mass spectrometry. Our data reveals that several mutations in IFT140 are hypomorphic and disrupt the stability of the IFT-A complex to varying degrees in a quantitative way. Allelic combination and the degree of IFT-A complex disruption in analysed missense mutations correlates with the severity of the observed phenotype in a subset of patients. In addition, we show that a distinct subset of mutations in IFT140 shows edgetic effects by disrupting specific PPIs rather than causing a total loss of IFT-A binding. This is the case e.g. with the disease-associated protein TULP3 which is involved in cilia-dependent sonic hedgehog signalling.
HostingRepositoryPRIDE
AnnounceDate2025-05-06
AnnouncementXMLSubmission_2025-05-06_11:49:52.097.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterTina Beyer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListacetylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-07-28 08:42:33ID requested
12025-05-06 11:49:53announced
Publication List
10.1016/j.mcpro.2025.100916;
Beyer T, Diwan GD, Leonhard T, Dahlke K, Klose F, Stehle IF, Seda M, Bolz S, Woerz F, Russell RB, Jenkins D, Ueffing M, Boldt K, Ciliopathy-Associated Missense Mutations in IFT140 are Tolerated by the Inherent Resilience of the IFT Machinery. Mol Cell Proteomics, 24(3):100916(2025) [pubmed]
Keyword List
submitter keyword: cilia,Intraflagellar transport, protein interaction, ciliopathy, hypomorph, missense mutation, edgetic
Contact List
Dr. Karsten Boldt
contact affiliationInstitute for Ophthalmic Research University of Tübingen
contact emailkarsten.boldt@uni-tuebingen.de
lab head
Tina Beyer
contact affiliationUniklinik Tübingen
contact emailtina.beyer@uni-tuebingen.de
dataset submitter
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