Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders

Sartor, Francesca; Anderson, Jihan; McCaig, Colin; Miedzybrodzka, Zosia; Müller, Berndt

doi:10.1042/bst20150168

Cited by 13 publications

(15 citation statements)

References 56 publications

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“…ID genes encode proteins involved in a variety of cellular processes which can be either 'neuron specific' such as synaptic proteins for instance but also more ubiquitous such as proteins involved in global regulation of gene expression at the transcriptional or post-transcriptional level. While the most frequent monogenic form of NDD, the fragile-X syndrome, is caused by mutations of FMRP, a ribosome-associated protein that regulates translation [7,8], the list of NDD-associated genes encoding members of RNA metabolism pathways, including those of mRNA decay and translation, is rapidly expanding [9,10]. This review will focus on a sub-set of the most recently identified ones ( Table 1).…”

Section: Introductionmentioning

confidence: 99%

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Weil

Piton

Lessel

et al. 2020

Biochemical Society Transactions

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Intellectual disability (ID) affects at least 1% of the population, and typically presents in the first few years of life. ID is characterized by impairments in cognition and adaptive behavior and is often accompanied by further delays in language and motor skills, as seen in many neurodevelopmental disorders (NDD). Recent widespread high-throughput approaches that utilize whole-exome sequencing or whole-genome sequencing have allowed for a considerable increase in the identification of these pathogenic variants in monogenic forms of ID. Notwithstanding this progress, the molecular and cellular consequences of the identified mutations remain mostly unknown. This is particularly important as the associated protein dysfunctions are the prerequisite to the identification of targets for novel drugs of these rare disorders. Recent Next-Generation sequencing-based studies have further established that mutations in genes encoding proteins involved in RNA metabolism are a major cause of NDD. Here, we review recent studies linking germline mutations in genes encoding factors mediating mRNA decay and regulators of translation, namely DCPS, EDC3, DDX6 helicase and ID. These RNA-binding proteins have well-established roles in mRNA decapping and/or translational repression, and the mutations abrogate their ability to remove 5′ caps from mRNA, diminish their interactions with cofactors and stabilize sub-sets of transcripts. Additional genes encoding RNA helicases with roles in translation including DDX3X and DHX30 have also been linked to NDD. Given the speed in the acquisition, analysis and sharing of sequencing data, and the importance of post-transcriptional regulation for brain development, we anticipate mutations in more such factors being identified and functionally characterized.

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Section: Introductionmentioning

confidence: 99%

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Weil

Piton

Lessel

et al. 2020

Biochemical Society Transactions

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“…Around 12% of single nucleotide mutations found in human gene mutation database will generate mRNAs with the PTCs ( 13 ), which are occasionally associated to human diseases, such as β-thalassemia and Duchenne muscular dystrophy ( 14 ). Furthermore, genetic mutations in components of the NMD machinery are implicated in human neurological disorders, immune diseases and cancers ( 5 , 15 ). Thus, understanding the biological functions and mechanisms of NMD would be beneficial for designing strategies to treat PTC-generated human diseases by manipulating NMD activity, and to cure human genetic disorders arising from mutations in NMD factors.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with UPF3B mutations manifest neurological symptoms, such as intellectual disability, schizophrenia and autism ( 112 , 113 ). Recent studies by genomic sequencing in human patients with neurodevelopmental disorders identify mutations in UPF2, UPF3A, SMG6, SMG9 and EJC component RBM8A, indicating that NMD is essential for mammalian brain development ( 15 , 114 , 115 ). Furthermore, since NMD participates in synapse architecture maintenance and synaptic vesicle recycling and is thus required for functions of mature neurons, the neurological symptoms in patients with NMD factor mutations could be due to synergistic effects of prenatal brain development abnormalities and postnatal neuronal dysfunctions ( 87 , 116 , 117 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, NMD inhibition in disease therapies should be applied with caution since knockdowns or knockouts of NMD factors in animal models indicate that NMD deficiency generates strong toxicities to cells as well as to tissues. Furthermore, deficiencies of different NMD factors in humans cause severe pathological symptoms in the central nervous system, as well as in the immune system ( 15 , 51 ). In this way, at current stage, a transcript-specific inhibition of NMD will have less adverse effects than general NMD inhibition ( 157 ).…”

Section: Introductionmentioning

confidence: 99%

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Nonsense-mediated mRNA decay: a ‘nonsense’ pathway makes sense in stem cell biology

Han

Wei

Wang

et al. 2017

Nucleic Acids Research

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Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional regulatory mechanism of gene expression in eukaryotes. Originally, NMD was identified as an RNA surveillance machinery in degrading ‘aberrant’ mRNA species with premature termination codons. Recent studies indicate that NMD regulates the stability of natural gene transcripts that play significant roles in cell functions. Although components and action modes of the NMD machinery in degrading its RNA targets have been extensively studied with biochemical and structural approaches, the biological roles of NMD remain to be defined. Stem cells are rare cell populations, which play essential roles in tissue homeostasis and hold great promises in regenerative medicine. Stem cells self-renew to maintain the cellular identity and differentiate into somatic lineages with specialized functions to sustain tissue integrity. Transcriptional regulations and epigenetic modulations have been extensively implicated in stem cell biology. However, post-transcriptional regulatory mechanisms, such as NMD, in stem cell regulation are largely unknown. In this paper, we summarize the recent findings on biological roles of NMD factors in embryonic and tissue-specific stem cells. Furthermore, we discuss the possible mechanisms of NMD in regulating stem cell fates.

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“…Indeed, mutations that affect translational control of mRNAs result in at least some forms of those pathologies (Sahin and Sur ; Sartor et al . ).…”

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confidence: 97%

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

Hetman

Słomnicki

2018

Journal of Neurochemistry

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Development of the nervous system is carried out by complex gene expression programs that are regulated at both transcriptional and translational level. In addition, quality control mechanisms such as the TP53-mediated apoptosis or neuronal activity-stimulated survival ensure successful neurogenesis and formation of functional circuitries. In the nucleolus, production of ribosomes is essential for protein synthesis. In addition, it participates in chromatin organization and regulates the TP53 pathway via the ribosomal stress response. Its tight regulation is required for maintenance of genomic integrity. Mutations in several ribosomal components and trans-acting ribosomal biogenesis factors result in neurodevelopmental syndromes that present with microcephaly, autism, intellectual deficits and/or progressive neurodegeneration. Furthermore, ribosomal biogenesis is perturbed by exogenous factors that disrupt neurodevelopment including alcohol or Zika virus. In this review, we present recent literature that argues for a role of dysregulated ribosomal biogenesis in pathogenesis of various neurodevelopmental syndromes. We also discuss potential mechanisms through which such dysregulation may lead to cellular pathologies of the developing nervous system including insufficient proliferation and/or loss of neuroprogenitors cells, apoptosis of immature neurons, altered neuronal morphogenesis, and neurodegeneration.

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Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders

Cited by 13 publications

References 56 publications

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Nonsense-mediated mRNA decay: a ‘nonsense’ pathway makes sense in stem cell biology

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

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