PXD012415

PXD012415 is an original dataset announced via ProteomeXchange.

Title	Dynamic role of Rotatin in mitosis, ciliogenesis and nucleokinesis correlates with variable mutant cerebral phenotypes.
Description	Recessive mutations in RTTN, encoding centrosome associated protein Rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time a wide variety of other brain malformations has been ascribed to RTTN mutations, such as primary microcephaly. However, the function of Rotatin is largely unknown and the molecular disease mechanism underlying these malformations has not yet been elucidated. Here, we report four novel families identified by high throughput sequencing, one of them with a novel deep intronic variant. We reviewed RTTN-related disease phenotypes and defined the spectrum which includes intellectual disability (ID), short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. Rotatin expression, function and cellular disease phenotype were studied in cultured primary skin fibroblasts from eight unrelated affected individuals. We found that Rotatin deficiency leads to abnormal centrosome amplification during mitosis, resulting in multipolar spindle formation, mitotic failure, increased apoptosis and aneuploidy. In non-dividing healthy cells, Rotatin localizes at the primary cilium, both at basal body and axoneme during ciliogenesis. Interestingly, interphase mutant cells show aberrant ciliogenesis. Proteomics analysis reveals that exogenous Rotatin in HEK293 cells interacts with the non-muscle cellular myosin complex (MYH9-MYH10-MYH14), which is essential for nucleokinesis during neuronal migration. In hiPSC-derived neurons, endogenous Rotatin localizes to the leading edge centrosome, which pulls the perinuclear cage during nucleokinesis, suggesting a pivotal role of Rotatin in neuronal migration. This study sheds light on the pleiotropic cellular functions of Rotatin, explaining disease spectrum linked to both neuronal proliferation and migration.
HostingRepository	PRIDE
AnnounceDate	2019-03-25
AnnouncementXML	Submission_2019-03-25_07:01:03.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jeroen Demmers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2019-01-17 06:13:01	ID requested
⏵ 1	2019-03-25 07:01:04	announced

Vandervore LV, Schot R, Kasteleijn E, Oegema R, Stouffs K, Gheldof A, Grochowska MM, van der Sterre MLT, van Unen LMA, Wilke M, Elfferich P, van der Spek PJ, Heijsman D, Grandone A, Demmers JAA, Dekkers DHW, Slotman JA, Kremers GJ, Schaaf GJ, Masius RG, van Essen AJ, Rump P, van Haeringen A, Peeters E, Altunoglu U, Kalayci T, Poot RA, Dobyns WB, Bahi-Buisson N, Verheijen FW, Jansen AC, Mancini GMS, Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics. Brain, 142(4):867-884(2019) [pubmed]

curator keyword: Biological

submitter keyword: Rotatin, mitosis, ciliogenesis, nucleokinesis

Jeroen Demmers
contact affiliation	Proteomics Center, Erasmus MC Rottrdam, the Netherlands
contact email	j.demmers@erasmusmc.nl
lab head
Jeroen Demmers
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/2019/03/PXD012415

PRIDE project URI

• PRIDE
  1. PXD012415
     1. Label: PRIDE project
     2. Name: Dynamic role of Rotatin in mitosis, ciliogenesis and nucleokinesis correlates with variable mutant cerebral phenotypes.