Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.

Introduction

Brain development is a complex and delicate process reliant upon fine modulation of gene expression. During neurodevelopment various regulatory pathways cooperate to establish the spatial and temporal gene expression patterns necessary for a properly connected neuronal network. Hence, during early stages of neuronal differentiation, the brain is particularly susceptible to even small changes in mRNA stability and translation [1].

A number of processes important for transcriptome regulation and protein synthesis regulate the fate of the transcripts in the eukaryotic cell and have been implicated in causation of neurodevelopmental disorders (NDDs).

Here we review findings that implicate mutations in components of major pathways and processes regulating mRNA metabolism as causal in NDD: mRNA nuclear export, splicing, nonsense-mediated decay and translation, with emphasis on mutations that have been linked to the latter two processes (Table 1). As this is a rapidly expanding area of great interest, we are unable to provide a comprehensive review in this limited space and apologize in advance for any omissions.

Table 1
Rare and frequent mutations in components of pathways and processes regulating mRNA metabolism and protein synthesis implicated in NDDs
Cellular process Gene NDD Genetic association References 
mRNA splicing RBFOX1 ASD, ID, ADHD, epilepsy, bipolar disorder, schizoaffective disorder and schizophrenia CNV (mostly deletion), SNP and translocation [3]** 
 PQBP1 Renpenning syndrome Insertion, missense mutation, deletion and duplication [6,7
mRNA export NXF5 ID Inversion, silent and missense mutation [9,10
  ID and autism Deletion [11
 XPO1 ASD SNP [12
  2p15p16.1-deletion syndrome Deletion [13
 THOC6 ID Missense mutation [14
nonsense-mediated mRNA decay RBM8A 1q21.1 deletion/ duplication syndrome 1q21.1 microdeletion and microduplication [16
  ID CN (copy number) gain and loss [17
  TAR syndrome (ID in 7% of cases) SNP, deletion, frameshift insertion and nonsense mutation [18
 eIF4AIII ID CN gain [17
 RNSP1 ID CN gain [17
 UPF3B XLID, XLID with features of FG or Lujan–Fryns syndromes, ASD, schizophrenia, ADHD, DD Nonsense and missense mutation [2228
 UPF3A ID CN loss [17
  neural tube defects 13q33–34 deletion [33
 UPF2 ID CN gain and loss [17
 SMG6 ID CN gain [17
mRNA translation initiation EIF4E ASD Linkage to 4q21–31 [43
  ASD Translocation, nt insertion in the promoter [44
  ASD SNP [45
 FMR1* Fragile X-syndrome Trinucleotide repeat expansion [51
 CYFIP1 ASD, schizophrenia CNV [53]** 
 PTEN PTEN Hamartoma Syndrome Germline mutation [55]** 
 TSC1/2 TSC Insertion, deletion, missense and nonsense mutation [50]** 
Cellular process Gene NDD Genetic association References 
mRNA splicing RBFOX1 ASD, ID, ADHD, epilepsy, bipolar disorder, schizoaffective disorder and schizophrenia CNV (mostly deletion), SNP and translocation [3]** 
 PQBP1 Renpenning syndrome Insertion, missense mutation, deletion and duplication [6,7
mRNA export NXF5 ID Inversion, silent and missense mutation [9,10
  ID and autism Deletion [11
 XPO1 ASD SNP [12
  2p15p16.1-deletion syndrome Deletion [13
 THOC6 ID Missense mutation [14
nonsense-mediated mRNA decay RBM8A 1q21.1 deletion/ duplication syndrome 1q21.1 microdeletion and microduplication [16
  ID CN (copy number) gain and loss [17
  TAR syndrome (ID in 7% of cases) SNP, deletion, frameshift insertion and nonsense mutation [18
 eIF4AIII ID CN gain [17
 RNSP1 ID CN gain [17
 UPF3B XLID, XLID with features of FG or Lujan–Fryns syndromes, ASD, schizophrenia, ADHD, DD Nonsense and missense mutation [2228
 UPF3A ID CN loss [17
  neural tube defects 13q33–34 deletion [33
 UPF2 ID CN gain and loss [17
 SMG6 ID CN gain [17
mRNA translation initiation EIF4E ASD Linkage to 4q21–31 [43
  ASD Translocation, nt insertion in the promoter [44
  ASD SNP [45
 FMR1* Fragile X-syndrome Trinucleotide repeat expansion [51
 CYFIP1 ASD, schizophrenia CNV [53]** 
 PTEN PTEN Hamartoma Syndrome Germline mutation [55]** 
 TSC1/2 TSC Insertion, deletion, missense and nonsense mutation [50]** 

*Frequent mutation; **Articles summarizing individual studies

mRNA splicing and NDD

mRNA splicing has a key role in regulating the neurogenic program. Alternative splicing allows the production of diverse mRNA and ultimately protein variants from the same pre-mRNA. Successful progression through neurodevelopmental stages and neuronal activity relies upon changes in the alternative splicing program. Mutations in genes RBFOX1 and PQBP1 encoding splicing factors have been implicated in NDDs.

RBFOX1 is a neuronal splicing factor that can enhance or repress alternative splicing and has additional roles in the regulation of mRNA stability and transcription [2]. RBFOX1 regulates extensive genetic programs important for neuron differentiation and maintenance [2]. Translocations, single nt polymorphisms (SNPs) and copy number variations (CNVs), mainly deletions, in RBFOX1 are associated with autism spectrum disorders (ASDs), intellectual disability (ID), attention deficit hyperactivity disorder (ADHD), epilepsy, bipolar disorder, schizoaffective disorder and schizophrenia (see study by Bill et al. [3] for a review reporting the individual studies). RBFOX1 mutation causing haploinsufficiency, probably in combination with other genetic or environmental factors, predisposes to NDDs [3]. Down-regulation of RBFOX1 expression and de-regulation of RBFOX1-dependent alternative splicing events were observed in post-mortem brains from subjects with ASD [4]. In vivo work supports the important role of RBFOX1 in the nervous system; deletion of RBFOX1 in mice increases neuronal excitability and susceptibility to seizures and impairs synaptic transmission [5].

Mutation in the splicing factor gene PQBP1 causes Renpenning syndrome or closely related X-linked ID (XLID) syndromes associated typically with microcephaly and short stature [6,7] (MIM 309500). PQBP1 regulates alternative splicing of targets that function in neurite morphogenesis and synaptic transmission and loss of PQBP1 in primary mouse neurons causes defects in neurite outgrowth [8].

NDD and nuclear export of mRNA

The transport of mRNA from the nucleus to the cytoplasm occurs through nuclear pore complexes and depends on the association with nuclear export receptors. Mutation in the nuclear export factor genes NXF5, XPO1 and THOC6 also predispose to NDDs. Inversions, point mutations and deletions in the NXF5 gene, with highest expression in the brain, have been associated with ID and ASD [911]. ASD is also significantly associated with a SNP in XPO1, the gene encoding exportin-1 which mediates nuclear export of proteins, rRNAs, small nuclear U RNAs and several specific mRNAs [12]. In addition, XPO1 haploinsufficiency is likely to contribute to the phenotype in the 2p15p16.1 microdeletion syndrome (MIM 612513), characterized by ID, ASD, microcephaly and congenital defects [13]. Furthermore, missense mutations in THOC6 were found in patients with ID [14]. THOC6 is a component of the THO complex which co-ordinates mRNA processing and export. The loss-of-function mutation in THOC6 causes mislocalization of the protein to the cytoplasm [14].

In conclusion, loss-of-function mutations in nuclear export factors probably predispose to NDDs by disturbing the delivery of cargos with important neuronal functions to the cytoplasm.

Defects in nonsense-mediated mRNA decay are linked to NDD

Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance pathway that leads to the degradation of transcripts harbouring premature termination codons (PTCs) [15]. The main function of NMD is to prevent the production of truncated proteins from transcripts containing PTCs that arise for example from frameshift or nonsense mutations or from errors in mRNA splicing. In addition, NMD plays a role in the regulation of expression of up to 10% of mRNAs. Such natural NMD targets are produced by alternative splicing or possess NMD-inducing features such as the presence of introns downstream of the stop codon, upstream ORFs (uORFs) or long 3′ untranslated regions (3′-UTRs). The NMD process is reviewed elsewhere in more detail [15].

Mutation of RBM8a, eIF4AIII, RNPS1, UPF3B, UPF3A, UPF2 and SMG6 genes in the NMD pathway has been linked to NDD. RBM8a, eukaryotic translation initiation factor (eIF4)AIII and RNPS1 proteins are components of the exon–junction complex (EJC) deposited 20–24 nts upstream of each exon–exon junction process during splicing. EJCs serve as a platform for the binding of NMD factors. In the absence of a PTC, the ribosomes remove the EJCs from the mRNA as the vast majority of normal stop codons are located in the last exon. However, if the ribosome stops at a PTC located in an upstream exon, EJCs remain associated with the mRNA and facilitate the interaction of UPF3B or UPF2 with UPF1. UPF1 is recruited to the terminating ribosome together with the release factors eRF1 (eRF, eukaryotic release factor) and eRF3 and the kinase SMG1 in form of the SMG1–UPF1–eRF1–eRF3 (SURF) complex. UPF2 promotes the phosphorylation of UPF1 by SMG1, leading to the recruitment of SMG5, SMG6 and SMG7 which mediate transcript decapping and/or deadenylation, leading to mRNA decay [15].

The EJC factor RBM8a is a binding partner of UPF3B. RBM8a is located in a region implicated in 1q21.1 deletion and duplication syndromes, in some cases associated with ID, ASD, schizophrenia and microcephaly (MIM 612474, MIM 612475) [16]. CNVs in RBM8a have been associated with ID [17] and compound inheritance of a low-frequency non-coding SNP and a null mutation in RBM8a causes Thrombocytopenia with absent radius syndrome (MIM 274000), a developmental disorder which co-occurs with ID in ∼7% of the cases [18]. Gain- and loss-of-function studies in mice show that RBM8a has an important role in the control of behaviour and neurogenesis. Overexpression of RBM8a protein in the dentate gyrus of adult mice increases anxiety-like behaviour, decreases social interaction behaviour, modulates neuroplasticity and enhances adult neurogenesis [19]. Consistently, RBM8A haploinsufficiency in the dorsal telencephalon in mice causes microcephaly and defects in neurogenesis [20].

Copy number gains in eIF4AIII and RNSP1 are associated with NDDs [17]. eIF4AIII depletion in rat neurons strengthens excitatory synaptic transmission and increases the abundance of glutamate receptors at the synapse [21]. The effects of the mutations in humans combined with findings from animal models indicate that EJC proteins are important for neuroplasticity through the control of neurogenesis and synaptic transmission [1921].

Mutation in genes encoding UPF3B, UPF3A, UPF2 and SMG6 is likewise associated with NDDs. Patients with nonsense and missense mutations in UPF3B were diagnosed with XLID (MIM 300676); with elements of FG and Lujan–Fryns syndromes (MIM305450, MIM309520) or with developmental delay (DD), ASD, schizophrenia and ADHD [2228]. UPF3B nonsense and missense mutations have been detected in 31 male patients in 12 affected families. UPF3B protein is not detectable and UPF3B mRNA levels are reduced in lymphoblastoid cell lines from patients carrying nonsense mutations, suggesting that UPF3B mRNA itself became an NMD target [2224]. Interestingly, the levels of the UPF3B paralogue, UPF3A, are elevated in the absence of UPF3B [29,30]. UPF3A can partially compensate for the loss of UPF3B in NMD [29]. Indeed, the severity of the phenotype associated with the loss of UPF3B is inversely proportional to UPF3A protein levels in cells from patients [30]. In these cells, approximately 5% of the transcriptome is de-regulated, indicating that despite UPF3A up-regulation, full UPF3B activity is necessary for proper transcriptome regulation by NMD [30].

Missense mutations in UPF3B linked to NDD are outside known functional domains but in conserved regions, suggesting they are important for UPF3B activity [31]. Recent work in our laboratory has shown that missense mutations impair the activity of UPF3B in NMD and expression of UPF3B with missense mutations alters the differentiation of neural stem cells, recapitulating the decreased connectivity observed in post-mortem brains from patients with NDDs [31,32].

Mutation of UPF3A is also linked to NDDs. UPF3A copy number losses are associated with ID [17] and deletion of the genomic region 13q33–34 encompassing UPF3A causes neural tube defects [33]. Additionally, CNV in UPF2 is associated with ID [17]. Lymphoblastoid cells from two patients with UPF2 deletions have reduced UPF2 mRNA and protein expression and global transcriptome analysis revealed a 2-fold difference in the expression of 10% of genes [17]. Copy number gains in SMG6 are associated with NDDs [17]. SMG6 is a candidate gene for the 17p13.3 microduplication syndrome associated to intellectual impairment and autism (MIM 613215). In Drosophila Upf2, Smg1 and Smg6 mutations impair the synaptic vesicle cycle and synaptic transmission at the neuromuscular junction (NMJ) [34]. Furthermore, Smg1 mutations disrupt retinal and NMJ synaptic transmission and NMJ synaptic architecture, highlighting the requirement of a functional NMD at both central and peripheral synapses [34].

NMD malfunction can predispose to NDDs by causing mis-expression of genes important for neuronal differentiation and synaptic connectivity. For example, mutations in UPF3B lead to the de-regulation of two NMD targets involved in Rho signalling; ARHGAP24 isoform 1 and Atf4 (activating transcription factor 4) [30,31]. Rho family GTPases play a major role in neurons through their control of cytoskeleton remodelling, which is important for neurite outgrowth and the regulation of synaptic connectivity [35]. ARHGAP24 is a GTPase-activating protein that down-regulates Rac1 (ras-related C3 botulinum toxin substrate 1) activity and is involved in the regulation of the actin cytoskeleton, cell polarity and migration. ARHGAP24 isoform 1 overexpression has been shown to decrease neuronal arborization [30]. The transcription factor Atf4 regulates the formation of synapses and dendritic spines at least in part through Cdc42 (cell division cycle 42), a Rho family GTPase that regulates actin organization [36].

Significantly, mutation of different genes in the NMD pathway can affect the expression of the same genes. Approximately 40% of the genes differently regulated in lymphoblastoid cells from patients with UPF2 deletion overlap with those de-regulated in cells from patients with UPF3B nonsense mutation [17]. Several of these genes are known to have important neuronal functions, for example in synaptic transmission, cytoskeleton remodelling and axon guidance [17]. In conclusion, mutation of genes involved in all steps of the NMD process, from EJC factors to UPF proteins and SMG effectors, can predispose to NDDs.

NMD regulation during neurodevelopment

Interestingly, NMD is down-regulated to allow neuronal differentiation to occur properly. Work by the Wilkinson laboratory and by our group has shown that NMD activity and the mRNA and protein levels of UPF3B and UPF1 decrease during neuronal differentiation [31,37]. Wilkinson and co-workers [37] showed that UPF1 promotes the self-renewal state of neural stem cells through the destabilization of NMD transcripts that promote differentiation, such as transforming growth factor (TGF)-β signalling inhibitors. NMD down-regulation during neuronal differentiation is mediated by a miRNA feedback circuitry, where miR-128 and miR-9 are targeting UPF1 and UPF3B mRNAs respectively [37]. miR-128 expression increases when the differentiation program is triggered and miR-128 de-regulation has been detected in post-mortem cortex tissue of individuals with ASD [37,38], suggesting a link between the control of NMD factors expression and ASD. Intriguingly, Jolly et al. [39] reported that loss of UPF3B in neural progenitor cells promotes self-renewal, indicating that NMD is in some cases also necessary for differentiation [31]. Thus, in the nervous system, NMD can be required to both promote and prevent neural differentiation.

NDD and control of translation initiation

Regulation of gene expression occurs also at the level of translation of mRNAs into proteins, a process that is principally regulated at the stage of translation initiation [40]. During translation initiation, the ribosome is recruited to the mRNA through the formation of the eIF complex eIF4F, for which eIF4E is critical. eIF4E is a 25-kDa protein which recognizes and binds to the 5′-cap of mRNA via the methyl-7-guanosine moiety. eIF4E, the scaffold protein eIF4G and the RNA-helicase eIF4A form the eIF4F complex. Binding of the small ribosomal subunit to eIF4F is followed by scanning along the mRNA 5′-UTR region to find the start codon, for translation elongation to start. For a review of steps and factors involved in translation initiation see the work conducted by Merrick [41].

eIF4E activity has a key role in learning and memory through its control of translation at the synapse [42]. Localized protein synthesis controls synaptic plasticity, a phenomenon which changes synaptic strength [42]. Recent evidence indicates that eIF4E has a role in the pathogenesis of ASD. The genomic region 4q21–31, encompassing the EIF4E gene, has been associated to ASD by a linkage study [43]. First direct evidence linking eIF4E protein to autism was reported by our group [44]. A boy with classic autism was found to have a reciprocal translocation between chromosomes 4 and 5, with the breakpoint site being mapped to the EIF4E region on chromosome 4q. Moreover, we found identical nt insertions in the EIF4E promoter in two autistic siblings and one parent from two unrelated families. This sequence variant results in an increase in EIF4E promoter activity, as identified by in vitro studies [44]. Subsequently, an intronic SNP in EIF4E was found significantly over-represented in a cohort of 605 patients with classic autism [45].

Studies in mice have shown that eIF4E overexpression or knockout of the eIF4E inhibitor 4EBP2 results in an increase in cap-dependent translation [46,47]. These mice exhibit repetitive patterns of behaviour and deficits in social interaction, behaviours consistent with ASD. Furthermore, synaptic dysfunction is observed in the cortex, striatum and hippocampus areas of the brain. In both animal models of increased eIF4E activity, there is an increase in translation of the synaptic adhesion protein neuroligin, also linked to ASD [48]. Interestingly, through the addition of 4EGI-1, an inhibitor of eIF4E activity that blocks eIF4E/eIF4G binding, the autistic behaviours exhibited in the mouse models are reversed [46,47]. Neuroligin protein levels are also reduced to wild-type levels [46]. Thus, these findings strongly suggest a link between de-regulated cap-dependent translation initiation and ASD. They also suggest that the defects caused are not permanent and can be corrected with pharmacological treatment.

Although basal amounts of eIF4E are sufficient for the translation of most cellular mRNAs, overexpression of eIF4E leads to the preferential translation of a subset of mRNAs whose 5′-UTR contain extensive secondary structures [49]. Neuroligin mRNAs are an example of eIF4E sensitive mRNAs with a unique repeated structural element within their mRNA 5′-UTR.

It is interesting to note that eIF4E is the final factor of the the PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR (mammalian target of rapamycin) pathway whose components have previously been implicated in autism (Figure 1) [50]. Following synaptic activity, the PI3K/AKT/mTOR pathway is stimulated, permitting the activation of eIF4E allowing protein synthesis to occur. Negative regulators in this pathway PTEN (phosphatase and tensin homologue) and tuberous sclerosis complex (TSC)1/2 as well as FMRP (fragile X mental retardation protein) are mutated in single gene disorders co-morbid with ASD [50]. FMRP is an RNA-binding protein encoded by the FMR1 gene, which is ubiquitously expressed in all cells, but predominantly in neurons [51]. In the brain, FMRP inhibits translation initiation by forming a complex with the 4EBP (eIF4E-binding protein)-like protein CYFIP1 (cytoplasmic FMR1 interacting protein 1) which interacts with eIF4E [52]. Loss of FMRP expression, commonly by expansion of a trinucleotide repeat in the 5′-UTR region of the FMR1 gene, causes Fragile X syndrome (MIM 309550) which is the most common disorder associated with ID and ASD [51]. The loss of FMRP abrogates the control of eIF4E by CYFIP1, leading to de-regulation of the control of synaptic translation. Additionally, CNVs in the CYFIP1 gene itself have been found to be associated with ASD and schizophrenia [53]. Increased protein synthesis as a result of hyperactivated PI3K/AKT/mTOR signalling de-regulates plasticity-related protein synthesis in neurons, leading to altered synaptic connectivity and cognitive impairment presenting itself as autism.

The PI3K/AKT/mTOR pathway controls synaptic protein synthesis and is implicated in ASD

Figure 1
The PI3K/AKT/mTOR pathway controls synaptic protein synthesis and is implicated in ASD

Following neurotransmitter release from the presynaptic terminal, activation of receptors such as metabotropic glutamate receptors (mGluRs) on the postsynaptic membrane leads to activation of PI3K. PI3K activity causes the activation of the kinase Akt whereas PTEN prevents Akt activation. TSC, a heterodimer of TSC1 and TSC2, is a substrate of Akt. When TSC is phosphorylated by Akt, its GTPase activating activity is inhibited, resulting in activation of its target G-protein Rheb (Ras homolog enriched in brain) and ultimately mTOR. mTOR can then phosphorylate 4EBPs. 4EBPs bind and sequester eIF4E when in an unphosphorylated state. When they are phosphorylated, eIF4E is released and able to interact with eIF4G to allow translation initiation to occur. FMRP interacts with the 4EBP CYFIP1 to control translation initiation. Genes framed are mutated in disorders associated with ASD.

Figure 1
The PI3K/AKT/mTOR pathway controls synaptic protein synthesis and is implicated in ASD

Following neurotransmitter release from the presynaptic terminal, activation of receptors such as metabotropic glutamate receptors (mGluRs) on the postsynaptic membrane leads to activation of PI3K. PI3K activity causes the activation of the kinase Akt whereas PTEN prevents Akt activation. TSC, a heterodimer of TSC1 and TSC2, is a substrate of Akt. When TSC is phosphorylated by Akt, its GTPase activating activity is inhibited, resulting in activation of its target G-protein Rheb (Ras homolog enriched in brain) and ultimately mTOR. mTOR can then phosphorylate 4EBPs. 4EBPs bind and sequester eIF4E when in an unphosphorylated state. When they are phosphorylated, eIF4E is released and able to interact with eIF4G to allow translation initiation to occur. FMRP interacts with the 4EBP CYFIP1 to control translation initiation. Genes framed are mutated in disorders associated with ASD.

Thus eIF4E, through its control of translation, has a crucial role at the synapse for correct neuronal functioning. Mutations found in eIF4E or in inhibitors of its activity have been reported in individuals with ASD. Excitingly, in cases of ASD caused by de-regulated translation initiation, pharmacological treatment to regulate translation either through eIF4E or upstream factors such as mTOR provides a potential therapeutic avenue [54]. Moreover, characterization of mRNAs which are targets of eIF4E overexpression could lead to the identification of molecules involved in neurodevelopment and to the development of autism biomarkers.

Conclusion

This review is a snapshot of current knowledge of genes linked to ASD, schizophrenia, ADHD and related neurodevelopmental syndromes that are involved in the post-transcriptional control of gene expression. Technical progress that has made possible studies such as the NHS 100000 genome project will lead to a more comprehensive view of the significance of these processes for the development of NDDs. Understanding how mutations in pathways that contribute to general gene expression predispose to NDDs is likely to depend on the identification of key genes whose expression is particularly sensitive to disturbance of said pathways and it is of fundamental importance to understand these effects. Correction of aberrant gene expression mechanisms itself offers a tantalizing opportunity for therapy.

We gratefully acknowledge support from Medical Research Scotland (grant PhD-654-2012) and Dundee Cell Products Ltd. FS was supported by the Fraserburgh Moonlight Prowl.

Abbreviations

     
  • 4EBP

    eIF4E-binding protein

  •  
  • ADHD

    attention deficit hyperactivity disorder

  •  
  • ASD

    autism spectrum disorder

  •  
  • Atf4

    activating transcription factor 4

  •  
  • CNV

    copy number variation

  •  
  • CYFIP1

    cytoplasmic FMR1-interacting protein 1

  •  
  • DD

    developmental delay

  •  
  • eIF

    eukaryotic translation initiation factor

  •  
  • EJC

    exon–junction complex

  •  
  • eRF

    eukaryotic release factor

  •  
  • FMRP

    fragile X mental retardation protein

  •  
  • ID

    intellectual disability

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • NDD

    neurodevelopmental disorder

  •  
  • NMD

    nonsense-mediated mRNA decay

  •  
  • NMJ

    neuromuscular junction

  •  
  • PI3K

    phosphatidylinositol 3-kinase

  •  
  • PTC

    premature termination codon

  •  
  • PTEN

    phosphatase and tensin homologue

  •  
  • SNP

    single nt polymorphism

  •  
  • TSC

    tuberous sclerosis complex

  •  
  • UTR

    untranslated region

  •  
  • XLID

    X-linked intellectual disability

Translation UK 2015: Held at the University of Aberdeen, U.K., 7–9 July 2015.

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