De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
Matilda A. Haas,
Linh Ngo,
Shan Shan Li,
Sibylle Schleich,
Zhengdong Qu,
Hannah K. Vanyai,
Hayley D. Cullen,
Aida Cardona-Alberich,
Ivan E. Gladwyn-Ng,
Alistair T. Pagnamenta,
Jenny C. Taylor,
Helen Stewart,
Usha Kini,
Kent E. Duncan,
Aurelio A. Teleman,
David A. Keays,
Julian I.-T. Heng
Affiliations
Matilda A. Haas
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
Linh Ngo
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
Shan Shan Li
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
Sibylle Schleich
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
Zhengdong Qu
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
Hannah K. Vanyai
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia
Hayley D. Cullen
The Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, WA 6009, Australia
Aida Cardona-Alberich
Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany
Ivan E. Gladwyn-Ng
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
Alistair T. Pagnamenta
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
Jenny C. Taylor
National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
Helen Stewart
Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK
Usha Kini
Department of Clinical Genetics, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK
Kent E. Duncan
Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany
Aurelio A. Teleman
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
David A. Keays
Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria
Julian I.-T. Heng
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
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.
