title: BOD1 Is Required for Cognitive Function in Humans and Drosophila.
abstract: Here we report a stop-mutation in the BOD1 (Biorientation Defective 1) gene, which co-segregates with intellectual disability in a large consanguineous family, where individuals that are homozygous for the mutation have no detectable BOD1 mRNA or protein. The BOD1 protein is required for proper chromosome segregation, regulating phosphorylation of PLK1 substrates by modulating Protein Phosphatase 2A (PP2A) activity during mitosis. We report that fibroblast cell lines derived from homozygous BOD1 mutation carriers show aberrant localisation of the cell cycle kinase PLK1 and its phosphatase PP2A at mitotic kinetochores. However, in contrast to the mitotic arrest observed in BOD1-siRNA treated HeLa cells, patient-derived cells progressed through mitosis with no apparent segregation defects but at an accelerated rate compared to controls. The relatively normal cell cycle progression observed in cultured cells is in line with the absence of gross structural brain abnormalities in the affected individuals. Moreover, we found that in normal adult brain tissues BOD1 expression is maintained at considerable levels, in contrast to PLK1 expression, and provide evidence for synaptic localization of Bod1 in murine neurons. These observations suggest that BOD1 plays a cell cycle-independent role in the nervous system. To address this possibility, we established two Drosophila models, where neuron-specific knockdown of BOD1 caused pronounced learning deficits and significant abnormalities in synapse morphology. Together our results reveal novel postmitotic functions of BOD1 as well as pathogenic mechanisms that strongly support a causative role of BOD1 deficiency in the aetiology of intellectual disability. Moreover, by demonstrating its requirement for cognitive function in humans and Drosophila we provide evidence for a conserved role of BOD1 in the development and maintenance of cognitive features.
authors.affiliation: Department for Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Sahar
authors.initials: S
authors.lastname: Esmaeeli-Nieh
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fenckova
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Iain M
authors.initials: IM
authors.lastname: Porter
authors.affiliation: Department for Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: M Mahdi
authors.initials: MM
authors.lastname: Motazacker
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Nijhof
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Castells-Nobau
authors.affiliation: Department Genetics, Aktogen Limited, University of Cambridge, Cambridge, United Kingdom.|Aktogen Hungary Ltd., Bay Zoltán Nonprofit Ltd., Institute for Biotechnology, Szeged, Hungary.|Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Asztalos
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Weißmann
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Farkhondeh
authors.initials: F
authors.lastname: Behjati
authors.affiliation: Department for Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
authors.affiliation: Department for Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Institut für Radiobiologie der Bundeswehr in Verbindung mit der Universität Ulm, München, Germany.
authors.forename: Harry
authors.initials: H
authors.lastname: Scherthan
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Seyed Morteza
authors.initials: SM
authors.lastname: Sayfati
authors.affiliation: Department for Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: H Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Swedlow
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.affiliation: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D003071:Cognition; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D007858:Learning; D051379:Mice; D008938:Mitosis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013569:Synapses / Q000235:genetics* / Q000473:pathology; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C524692:Bod1 protein, human