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Cell Rep. 2016 Jun 7;15(10):2251-2265. doi: 10.1016/j.celrep.2016.04.090. Epub 2016 May 26.

De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation.

Author information

1
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
2
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia.
3
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
4
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia.
5
Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
6
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
7
Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.
8
Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria.
9
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia. Electronic address: julian.heng@perkins.uwa.edu.au.

Abstract

Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons. We characterized de novo missense mutations in DENR (p.C37Y and p.P121L) detected in two unrelated human subjects diagnosed with brain developmental disorder to find that each variant impairs the function of DENR in mRNA translation re-initiation and disrupts the migration and terminal branching of cortical neurons in different ways. Thus, our findings link human brain disorders to impaired mRNA translation re-initiation through perturbations in DENR (OMIM: 604550) function in neurons.

PMID:
27239039
PMCID:
PMC4906373
DOI:
10.1016/j.celrep.2016.04.090
[Indexed for MEDLINE]
Free PMC Article

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