期刊
BRAIN
卷 140, 期 -, 页码 940-952出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx014
关键词
PRUNE1; microcephaly; developmental delay; normal brain development; microtubule polymerization; tubulinopathy
资金
- Medical Research Council [G1002279, G1001931]
- Wellcome Trust [WT093205 MA, WT104033AIA, WT098051]
- Newlife Foundation for Disabled Children
- Associazione per la Ricerca sul Cancro IG [11963]
- PRIN [E5AZ5F]
- FP7-Tumic [HEALTH-F2-2008-201662]
- Fondazione Adolfo Volpe e Associazione Pediatri di famiglia
- POR Rete delle Biotecnologie in Campania Movie
- Regione Campania
- European School of Molecular Medicine SEMM
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- US National Human Genome Research Institute/National Heart Lung Blood Institute [HG006542]
- Medical Research Council [G108/638, MR/J004758/1, G1001931, G1001253, G1002279, MR/K000608/1, G0802760] Funding Source: researchfish
- Muscular Dystrophy UK [16GRO-PS36-0055] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10082] Funding Source: researchfish
- MRC [G1001253, MR/K000608/1, G1002279, G0802760, MR/J004758/1, G108/638, G1001931] Funding Source: UKRI
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.
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