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Brain. 2019 Apr 1;142(4):867-884. doi: 10.1093/brain/awz045.

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

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Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), CA Rotterdam, The Netherlands.
Neurogenetics Research Group, Research Cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.
Center for Medical Genetics, UZ Brussel, Brussels, Belgium.
Department of Pathology, Clinical Bio-informatics, Erasmus University Medical Center (Erasmus MC), CA Rotterdam, The Netherlands.
Dipartimento della Donna, del Bambino, di Chirurgia Generale e Specialistica, Seconda Università degli studi della Campania "L. Vanvitelli", Naples, Italy.
Department of Molecular Genetics, Proteomics Center, Erasmus University Medical Center (Erasmus MC), CA Rotterdam, The Netherlands.
Department of Pathology, Optical Imaging Center, Erasmus University Medical Center (Erasmus MC), CA Rotterdam, The Netherlands.
Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center (Erasmus MC), 3015 CN Rotterdam, The Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, RB, Groningen, The Netherlands.
Department of Clinical Genetics, LUMC, Leiden University Medical Center, Postzone K-5-R, Postbus 9600, RC Leiden, The Netherlands.
Department of Pediatric Neurology, Juliana Hospital, Els Borst-Eilersplein 275, 2545 AA Den Haag, The Netherlands.
Department of Medical genetics, Istanbul Medical Faculty, Istanbul University, Topkapı Mahallesi, Turgut Özal Millet Cd, 34093 Fatih/İstanbul, Turkey.
Department of Cell biology, Erasmus University Medical Center (Erasmus MC), CA Rotterdam, The Netherlands.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Imagine Institute, INSERM UMR-1163, Laboratory Genetics and Embryology of Congenital Malformations, Paris Descartes University, Institut des Maladies Génétiques 24, Boulevard de Montparnasse, Paris, France.
Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium.

Erratum in


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 has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.


RTTN ; MYH10; centrosome amplification; microcephaly; mitosis

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