Dataset Information

Dynamic role of Rotatin in mitosis, ciliogenesis and nucleokinesis correlates with variable mutant cerebral phenotypes.

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD012415 | Pride | 2019-03-25

REPOSITORIES: Pride

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			Action	DRS
	1849_F_LauraVandervore_01.raw	Raw
	1849_F_LauraVandervore_02.raw	Raw
	1849_F_LauraVandervore_03.raw	Raw
	1878_F_LauraVandervore_01.raw	Raw
	1878_F_LauraVandervore_02.raw	Raw

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Publications

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics.

Vandervore Laura V LV Schot Rachel R Kasteleijn Esmee E Oegema Renske R Stouffs Katrien K Gheldof Alexander A Grochowska Martyna M MM van der Sterre Marianne L T MLT van Unen Leontine M A LMA Wilke Martina M Elfferich Peter P van der Spek Peter J PJ Heijsman Daphne D Grandone Anna A Demmers Jeroen A A JAA Dekkers Dick H W DHW Slotman Johan A JA Kremers Gert-Jan GJ Schaaf Gerben J GJ Masius Roy G RG van Essen Anton J AJ Rump Patrick P van Haeringen Arie A Peeters Els E Altunoglu Umut U Kalayci Tugba T Poot Raymond A RA Dobyns William B WB Bahi-Buisson Nadia N Verheijen Frans W FW Jansen Anna C AC Mancini Grazia M S GMS

Brain : a journal of neurology 20190401 4

Recessive mutations in RTTN, encoding the 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, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations ...[more]

PMID: 30879067

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