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

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

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 th...

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Main Authors: Haas, Matilda A., Ngo, Linh, Li, Shan Shan, Schleich, Sibylle, Qu, Zhengdong, Vanyai, Hannah K., Cullen, Hayley D., Cardona-Alberich, Aida, Gladwyn-Ng, Ivan E., Pagnamenta, Alistair T., Taylor, Jenny C., Stewart, Helen, Kini, Usha, Duncan, Kent E., Teleman, Aurelio A., Keays, David A., Heng, Julian I.-T.
Format: Online
Language:English
Published: Cell Press 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906373/
id pubmed-4906373
recordtype oai_dc
spelling pubmed-49063732016-06-22 De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation Haas, Matilda A. Ngo, Linh Li, Shan Shan Schleich, Sibylle Qu, Zhengdong Vanyai, Hannah K. Cullen, Hayley D. Cardona-Alberich, Aida Gladwyn-Ng, Ivan E. Pagnamenta, Alistair T. Taylor, Jenny C. Stewart, Helen Kini, Usha Duncan, Kent E. Teleman, Aurelio A. Keays, David A. Heng, Julian I.-T. Article 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. Cell Press 2016-05-26 /pmc/articles/PMC4906373/ /pubmed/27239039 http://dx.doi.org/10.1016/j.celrep.2016.04.090 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Haas, Matilda A.
Ngo, Linh
Li, Shan Shan
Schleich, Sibylle
Qu, Zhengdong
Vanyai, Hannah K.
Cullen, Hayley D.
Cardona-Alberich, Aida
Gladwyn-Ng, Ivan E.
Pagnamenta, Alistair T.
Taylor, Jenny C.
Stewart, Helen
Kini, Usha
Duncan, Kent E.
Teleman, Aurelio A.
Keays, David A.
Heng, Julian I.-T.
spellingShingle Haas, Matilda A.
Ngo, Linh
Li, Shan Shan
Schleich, Sibylle
Qu, Zhengdong
Vanyai, Hannah K.
Cullen, Hayley D.
Cardona-Alberich, Aida
Gladwyn-Ng, Ivan E.
Pagnamenta, Alistair T.
Taylor, Jenny C.
Stewart, Helen
Kini, Usha
Duncan, Kent E.
Teleman, Aurelio A.
Keays, David A.
Heng, Julian I.-T.
De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
author_facet Haas, Matilda A.
Ngo, Linh
Li, Shan Shan
Schleich, Sibylle
Qu, Zhengdong
Vanyai, Hannah K.
Cullen, Hayley D.
Cardona-Alberich, Aida
Gladwyn-Ng, Ivan E.
Pagnamenta, Alistair T.
Taylor, Jenny C.
Stewart, Helen
Kini, Usha
Duncan, Kent E.
Teleman, Aurelio A.
Keays, David A.
Heng, Julian I.-T.
author_sort Haas, Matilda A.
title De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
title_short De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
title_full De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
title_fullStr De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
title_full_unstemmed De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation
title_sort de novo mutations in denr disrupt neuronal development and link congenital neurological disorders to faulty mrna translation re-initiation
description 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.
publisher Cell Press
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906373/
_version_ 1613594153487171584

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