title: De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation.
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.
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Matilda A
authors.initials: MA
authors.lastname: Haas
authors.affiliation: 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.
authors.forename: Linh
authors.initials: L
authors.lastname: Ngo
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Shan Shan
authors.initials: SS
authors.lastname: Li
authors.affiliation: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schleich
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Qu
authors.affiliation: The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Vanyai
authors.affiliation: The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Hayley D
authors.initials: HD
authors.lastname: Cullen
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Aida
authors.initials: A
authors.lastname: Cardona-Alberich
authors.affiliation: 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.
authors.forename: Ivan E
authors.initials: IE
authors.lastname: Gladwyn-Ng
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Alistair T
authors.initials: AT
authors.lastname: Pagnamenta
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Duncan
authors.affiliation: German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
authors.affiliation: Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria.
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
authors.affiliation: 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.
authors.forename: Julian I-T
authors.initials: JI
authors.lastname: Heng
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002540:Cerebral Cortex / Q000196:embryology / Q000473:pathology; D039642:Eukaryotic Initiation Factors / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000151:congenital* / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C000622705:Denr protein, mouse; D039642:Eukaryotic Initiation Factors; D050505:Mutant Proteins; D012333:RNA, Messenger