PXD036304-1

PXD036304 is an original dataset announced via ProteomeXchange.

Title	Distinct spectrum of ciliopathic diseases results from de novoTUBB4B variants through differential effects on organelle-specific microtubules
Description	Microtubules are ancient and highly conserved polymers composed of alpha and beta tubulin heterodimers. Their dynamic remodelling drives diverse cellular processes from organelle trafficking and chromosome segregation to templating more stable structures like those of centrioles and ciliary axonemes. While organisms like Chlamydomonas reinhardtii only have a single - and -tubulin gene, TUBB4B, is one of 10 human -tubulin isotypes which can pair with one of the 9 isotypes of -tubulin. Whether this diversification permits discrete transcriptional units for cell type specific expression, or whether additional functional differences exist between isotypes remains unclear. Here, using human disease genetics, we reveal three distinct classes of ciliopathic disease in human patients carrying de novo mutations in TUBB4B. Using structure-function studies, we demonstrate these mutations differentially affect microtubule dynamics and cilia formation in a dominant negative manner. Importantly, using patient-modelled mutant as well as knockout Tubb4b mice we establish a necessary and non-redundant function for TUBB4B in building centrioles and axonemes of multiciliated cells. Our results suggest that a functional difference in TUBB4B is required to support the unique microtubule architecture in motile ciliated cells. It places primary ciliary dyskinesia and the ciliopathies more broadly into an expanding phenotypic and clinical spectrum of human tubulinopathies.
HostingRepository	PRIDE
AnnounceDate	2024-01-30
AnnouncementXML	Submission_2024-01-30_04:14:02.278.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex von kriegsheim
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-25 14:58:02	ID requested
⏵ 1	2024-01-30 04:14:02	announced
2	2024-10-22 06:28:07	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Tubulin,Cilia

Alex von Kriegsheim
contact affiliation	University of Edinburgh
contact email	avonkri@ed.ac.uk
lab head
Alex von kriegsheim
contact affiliation	University of Edinburgh
contact email	alex.vonkriegsheim@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036304
     1. Label: PRIDE project
     2. Name: Distinct spectrum of ciliopathic diseases results from de novoTUBB4B variants through differential effects on organelle-specific microtubules