BOD1 Is Required for Cognitive Function in Humans and Drosophila

• DOI: 10.1371/journal.pgen.1006022
• Publication Date: 2016-05-11T17:44:46Z
• Authors: Sahar Esmaeeli-Nieh; Michaela Fenckova; Iain M. Porter; M. Mahdi Motazacker; Bonnie Nijhof; Anna Castells-Nobau; Zoltan Asztalos; Robert Weißmann; Farkhondeh Behjati; Andreas Tzschach; Ute Felbor; Harry Scherthan; Seyed Morteza Say...; H. Hilger. Ropers; Kimia Kahrizi; Hossein Najmabadi; Jason R. Swedlow; Annette Schenck; Andreas W. Kuss
• Keywords: PLK1

Here we report a stop-mutation in the BOD1 (Biorientation Defective 1) gene, which co-segregates with intellectual disability large consanguineous family, where individuals that are homozygous for mutation have no detectable mRNA or protein. The protein is required proper chromosome segregation, regulating phosphorylation of PLK1 substrates by modulating Protein Phosphatase 2A (PP2A) activity during mitosis. We fibroblast cell lines derived from carriers show aberrant localisation cycle kinase and its phosphatase PP2A at mitotic kinetochores. However, contrast to arrest observed BOD1-siRNA treated HeLa cells, patient-derived cells progressed through mitosis apparent segregation defects but an accelerated rate compared controls. relatively normal progression cultured line absence gross structural brain abnormalities affected individuals. Moreover, found adult tissues expression maintained considerable levels, expression, provide evidence synaptic localization Bod1 murine neurons. These observations suggest plays cycle-independent role nervous system. To address this possibility, established two Drosophila models, neuron-specific knockdown caused pronounced learning deficits significant synapse morphology. Together our results reveal novel postmitotic functions as well pathogenic mechanisms strongly support causative deficiency aetiology disability. demonstrating requirement cognitive function humans conserved development maintenance features.