Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Reijnders, Margot R.F.; Kousi, Maria; Woerden, Geeske M. van; Klein, Marieke; Bralten, Janita; Mancini, Grazia M.S.; Essen, Ton van; Onori, Martina Proietti; Smeets, Eric; Gastel, M. van; Stegmann, Alexander P.A.; Stevens, Servi J.C.; Lelieveld, Stefan H.; Gilissen, Christian; Pfundt, Rolph; Tan, Perciliz L.; Kleefstra, Tjitske; Franke, Barbara; Elgersma, Ype; Katsanis, Nicholas; Brunner, Han G.

doi:10.1038/s41467-017-00933-6

Cited by 65 publications

(96 citation statements)

References 69 publications

(79 reference statements)

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“…Accordingly, many ASD genes are synaptic proteins, chromatin remodelers, or FMRP targets, that is genes encoding transcripts that bind to FMRP (Iossifov et al, ). Alterations of the same classes of protein functions and biological processes involved in neuronal development, such as the mammalian target of rapamycin (mTOR) pathways, GABA receptor function or glutamate NMDA receptor function, have been also found implicated in ID, epilepsy, and schizophrenia (Cristino et al, ; Endele et al, ; Gilman et al, ; Krumm et al, ; Paoletti, Bellone, & Zhou, ; Reijnders et al, ). The multiple genes and molecular pathways shared by ID, ASD, and other developmental or psychiatric disorders indicate a common origin that explains the co‐occurrence of these conditions (Barabási, Gulbahce, & Loscalzo, ; Cukier et al, ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

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Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low‐cost next‐generation sequencing gene panel that has been transferred into clinical practice, replacing single disease‐gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease‐gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease‐causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

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Section: Introductionmentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

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“…To further study the mechanisms of epileptogenesis and hyperexcitability in mTORopathies vs GATORopathies, a plasmid encoding a constitutively active form of the mTOR activator Rheb (Rheb CA ,) was introduced to the fetal mouse brain by in utero electroporation. Rheb was selected for comparative genetic manipulation because two recent studies have reported gain‐of‐function mutations in RHEB leading to MCD associated with epilepsy and because Rheb integrates both the canonical growth factor signaling vector and the ATP‐AMP‐AMPK‐dependent vector, thus allowing comparison with the amino acid signaling arm of the mTOR pathway. In addition, from a methodologic perspective, Rheb CA expression rapidly (6‐8 hours) activates the mTOR pathway as compared to other experimental strategies such as conditional transgenic mice, small hairpin RNA (shRNA), or CRISPR/Cas9 vectors because the timing of mTORC1 activation depends on the half‐life of the KD/KO protein of interest.…”

Section: Epileptogenesis and Mtor‐gator Signalingmentioning

confidence: 99%

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

et al. 2019

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The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.

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“…Specifically, we observed that these genomic regions are significantly enriched for an mTOR signaling gene set as well as for genes involved in cholesterol metabolism (see Figure 6a and Table S10). Regarding the mTOR gene set, the MTOR gene is itself an intellectual disability gene that has been intimately linked to brain development 84,85 . Regarding the cholesterol metabolism gene set, the brain contains approximately 25% of the body's cholesterol (mostly as a component of the myelin sheaths that surround axons) 86,87 with defects in brain cholesterol metabolism being linked to central nervous system disease 88,89 , and BCL11A has recently been shown to influence (and be influenced by) lipid levels [90][91][92] .…”

Section: Analysis Of 46 Diseases and Complex Traitsmentioning

confidence: 99%

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

Reshef

Finucane

Kelley

et al. 2017

Preprint

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Biological interpretation of GWAS data frequently involves analyzing unsigned genomic annotations comprising SNPs involved in a biological process and assessing enrichment for disease signal. However, it is often possible to generate signed annotations quantifying whether each SNP allele promotes or hinders a biological process, e.g., binding of a transcription factor (TF). Directional effects of such annotations on disease risk enable stronger statements about causal mechanisms of disease than enrichments of corresponding unsigned annotations. Here we introduce a new method, signed LD profile regression, for detecting such directional effects using GWAS summary statistics, and we apply the method using 382 signed annotations reflecting predicted TF binding. We show via theory and simulations that our method is well-powered and is well-calibrated even when TF binding sites co-localize with other enriched regulatory elements, which can confound unsigned enrichment methods. We apply our method to 12 molecular traits and recover many known relationships including positive associations between gene expression and genome-wide binding of RNA polymerase II, NF-κB, and several ETS family members, as well as between known chromatin modifiers and their respective chromatin marks. Finally, we apply our method to 46 diseases and complex traits (average N = 289, 617) and identify 77 significant associations at per-trait FDR < 5%, representing 12 independent signals. Our results include a positive association between educational attainment and genome-wide binding of BCL11A, consistent with recent work linking BCL11A hemizygosity to intellectual disability; a negative association between lupus risk and genome-wide binding of CTCF, which has been shown to suppress myeloid differentiation; and a positive association between Crohn's disease (CD) risk and genome-wide binding of IRF1, an immune regulator that lies inside a CD GWAS locus and has eQTLs that increase CD risk. Our method provides a new way to leverage functional data to draw inferences about causal mechanisms of disease.

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Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

Cited by 65 publications

References 69 publications

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

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