Autism presenting in the context of a genetic variant of CFTR and early HSV exposure confounded by chronic pain, altered gut microbiota and paternal abandonment; limitations of current pharmacotherapy and barriers to personalized treatment recommendations

Deutsch, Stephen I.; Kreiser, Nicole L.; Urbano, Maria R.; Burket, Jessica A.; Pickle, Jerrah C.

doi:10.1016/j.pmip.2017.07.002

Cited by 4 publications

(5 citation statements)

References 25 publications

(58 reference statements)

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“…We also identify a number of genes ( CGN , CYP11B2 , DNAH5 , DNAH7 , DNAH11 , DNMT3B , GPX2 , and PTGS1 ) with paralogs listed in the SFARI Human Gene Module. Some high evidence XenoReg have polymorphisms and rare variants ( ADSL , CBS, CFTR , CHST5 , CYP1A2 , CYP2R1, GSTM1, GUSB, NOS2 , STS , and SYN1 ) or altered expression levels ( AFDN , CLDN3, PTGES3 , and VWF ) associated with ASD ( Kim et al, 2008 ; O’Roak et al, 2012 ; Braam et al, 2013 ; Schmidt et al, 2015 ; Woodbury-Smith et al, 2015 ; Chatterjee et al, 2016 ; Fiorentino et al, 2016 ; Patel et al, 2016 ; Deutsch et al, 2017 ; Niego and Benítez-Burraco, 2021 ). The predicted damaging variants uncovered in this study provide supportive evidence for their role in ASD risk, particularly in the context of early life exposure to xenobiotics.…”

Section: Discussionmentioning

confidence: 99%

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

et al. 2022

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Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

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Section: Discussionmentioning

confidence: 99%

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

et al. 2022

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“…Six of these genes, namely HDAC4, MECP2, TCF4, TRIM33, TTN, and TSC2, belong to the SFARI category 1-2 (highconfidence and strong candidate genes) and are widely associated with the neuropathological mechanisms of ASD [31,[52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]. The CFTR, NOD2, PPP2R2B, and TTR genes were not found in the SFARI databases, and data on the role of 11 Disease Markers these genes in ASD are very sparse [71,72]. However, although the exact mechanism is not clear, there is some evidence of a link between these genes and ASD.…”

Section: Discussionmentioning

confidence: 99%

“…This study showed that CFTR has an early and widespread distribution during development. In addition, a case of autism associated with a genetic variant of CFTR and early exposure to herpes simplex virus (HSV) has been described [ 71 ]. The NOD2 gene belongs to the intracellular NOD-like receptor family and plays an important role in the immune response to intracellular bacterial lipopolysaccharides (LPS) [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan

Perfilyeva¹,

Bespalova

Perfilyeva

et al. 2022

Disease Markers

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The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The variants were analyzed in the context of gene networks and pathways. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms.

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“…Gastrointestinal complaints occur commonly in persons with ASD, arousing interest in possible pathogenic consequences of abnormalities of “tight junctions” between intestinal epithelial cells leading to disruption of the gut-blood barrier, as well as alterations of the gut microbiota [ 52 , 53 , 54 , 55 ]. With respect to the gut microbiota, a recent study suggested that p-cresol, a neurotoxin produced by several species of Clostridium that differentially alters relative expression of GluN2B and GluN2A NMDA receptor subunits to each other in hippocampus and nucleus accumbens of “control” Wistar and audiogenic seizure-prone Krushinski–Molodkina (KM) rats [ 52 ].…”

Section: P-cresol a Pharmacological Tool To Disturb The Balance Betwe...mentioning

confidence: 99%

Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches

2022

Self Cite

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Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through different mechanisms, they share the pathogenic consequences of causing disturbance of highly regulated NMDA receptor activation. Disturbances of NMDA receptor activation due to sequence variants, protein termination variants and copy number variants are often cell-specific and regionally selective. Thus, translational therapeutic NMDA receptor agonist interventions, which may require chronic administration, must have specificity, selectivity and facilitate NMDA receptor activation in a manner that is physiologic (i.e., mimicking that of endogenously released glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). Importantly, knockout mice with absent expression and mice with haploinsufficient expression of the deleterious genes often serve as good models to test the potential efficacy of promising pharmacotherapeutic strategies. The Review considers diverse examples of “illness” genes, their pathogenic effects on NMDA receptor activation and, when available, results of studies of impaired sociability in mouse models, including “proof of principle/proof of concept” experiments exploring NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for developing an inventory of PAMs and negative allosteric modulators (NAMs) for translational therapeutic intervention. Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors.

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Autism presenting in the context of a genetic variant of CFTR and early HSV exposure confounded by chronic pain, altered gut microbiota and paternal abandonment; limitations of current pharmacotherapy and barriers to personalized treatment recommendations

Cited by 4 publications

References 25 publications

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan

Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches

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