PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment
Di Somma, A
Mohan Mohapatra, T
Kumar Rai, S
Di Rosa, G
Oxford University Press (OUP) for Guarantors of Brain
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.
This study was supported by the Medical Research Council (G1002279 to A.H.C.) (G1001931 to E.L.B.), Wellcome Trust strategic award (Synaptopathies, WT093205 MA and WT104033AIA), Newlife Foundation for Disabled Children (A.H.C. and E.L.B.) , Associazione per la Ricerca sul Cancro IG: 11963 (AIRC-MZ), PRIN (E5AZ5F) 2008 (M.Z.), FP7- Tumic HEALTH-F2-2008- 201662 (M.Z.), Fondazione Adolfo Volpe e Associazione Pediatri di famiglia (M.Z.), POR Rete delle Biotecnologie in Campania Movie (M.Z.), Regione Campania legge n.5 (M.Z.), Wellcome Trust (WT098051), European School of Molecular Medicine SEMM for the fellowship (V.F.), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and by the US National Human Genome Research Institute/National Heart Lung Blood Institute (HG006542 to the Baylor Hopkins Center for Mendelian Genomics).
This is the final version of the article. Available from OUP via the DOI in this record.
Vol. 140 (4), pp. 940 - 952
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