Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Costain, Gregory; Walker, Susan; Argiropoulos, Bob; Baribeau, Danielle A.; Bassett, Anne S.; Boot, Erik; Devriendt, Koen; Kellam, Barbara; Marshall, Christian R.; Prasad, Aparna; Serrano, Moises A.; Stavropoulos, Dimitri J.; Twede, Hope; Vermeesch, Joris Robert; Vorstman, Jacob; Scherer, Stephen W.

doi:10.1186/s11689-019-9263-3

Cited by 7 publications

(5 citation statements)

References 88 publications

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“…This would be in line with others, who propose the ADP:ATP ratio as an indicator of cell viability, necrosis and apoptosis (73). As being ubiquitously expressed (74), DMXL2 is associated with several conditions (75)(76)(77)(78)(79)(80)(81)(82)(83) and is regarded as a functional biomarker of estrogen receptor alpha (Erα) positive breast cancer (71). DMXL2 drives NOTCH signalling and the mesenchymal switch in endocrine therapy-resistant breast cancer cells when overexpressed (71).…”

Section: Discussionsupporting

confidence: 76%

Short- and long-term effects of radiation exposure at low dose and low dose rate in normal human VH10 fibroblasts

Akuwudike,

López-Riego,

Marczyk

et al. 2023

Front. Public Health

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IntroductionExperimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.MethodsHuman VH10 skin fibroblasts exposed to 25, 50, and 100 mGy of 137Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e., discovery (n = 30) and validation (n = 12), were subjected to RNA sequencing. The pool of the results from those six experiments with shared conditions (1.6 mGy/h; 24 h), together with an earlier time point (0 h), constituted a third cohort (n = 12).ResultsThe 100 mGy-exposed cells at all abovementioned dose rates, harvested at 0/24 h and 21 days after exposure, showed no strong gene expression changes. DMXL2, involved in the regulation of the NOTCH signaling pathway, presented a consistent upregulation among both the discovery and validation cohorts, and was validated by qPCR. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort (p = 0.76, normalized enrichment score (NES) = 0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. Concurringly, cell viability assays, performed 1, 3, and 6 days post irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects on cell growth or survival patterns. Tendencies of increased viability (day 6) and reduced colony size (day 21) were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure.DiscussionIn conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on radioresistant VH10 cells.

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Section: Discussionsupporting

confidence: 76%

Short- and long-term effects of radiation exposure at low dose and low dose rate in normal human VH10 fibroblasts

Akuwudike,

López-Riego,

Marczyk

et al. 2023

Front. Public Health

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“…DMXL2 is also a NDD risk gene, with copy number variations and de novo missense mutations observed in individuals with ASD (Costain, Walker, & Argiropoulos, 2019;Iossifov, O'Roak, & Sanders, 2014;Krumm, Turner, & Baker, 2015). Additionally, biallelic loss of function mutations in DMXL2 are associated with Ohtahara syndrome, which is characterized by severe epileptic encephalopathy (Esposito, Falace, & Wagner, 2019) (Figure 3).…”

Section: V-atpasementioning

confidence: 99%

“…For example, defects in local synaptic protein synthesis have been identified in monogenic models of NDDs such as FXS, Angelman syndrome and Tuberous Sclerosis (Louros & Osterweil, 2016). Indeed, altered function of key postsynaptic protein synthesis regulatory pathways such as mammalian target of rapamycin and mGluR signalling are considered to be a point of pathogenic convergence for many NDDs (Costa‐Mattioli & Monteggia, 2013). Dysregulation of protein translation at the presynapse may also occur in NDDs, since nerve terminals were recently demonstrated to contain both ribosomes and mRNA (Hafner, Donlin‐Asp, Leitch, Herzog, & Schuman, 2019).…”

Section: From Dysregulated Sv Recycling To Neurodevelopmental Disordersmentioning

confidence: 99%

Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle

Bonnycastle

Davenport

Cousin

2020

Journal of Neurochemistry

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The evoked release of neurotransmitter in response to action potential invasion at the presynapse is an essential component of brain function. Neurotransmitter release is controlled by the recycling of synaptic vesicles (SVs), a process that comprises a series of intricate molecular events that are coupled to neuronal activity both temporally and spatially. Because of its critical importance in maintaining the fidelity of neurotransmission, the assumption was that individuals harbouring mutations within key SV recycling genes would not be identified. However strong evidence has emerged that, rather than being incompatible with life, mutations in the most essential of SV recycling genes precipitate a series of neurodevelopmental disorders (NDDs).NDDs are a series of heterogeneous disorders that can be grouped by the presentation of abnormal brain development (Krol &

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“…In addition to genetic risk variants, haploinsufficiency of dose‐response genes may contribute to a certain phenotype (Costain et al, ). Our patients are hemizygous for TFRC.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

Malt

Frengen

Wangensteen

et al. 2019

Molec Gen & Gen Med

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Background Genetic risk variants in the hemizygous allele may influence neuropsychiatric manifestations and clinical course in 3q29 deletion carriers. Methods In‐depth phenotypic assessment in two deletion carriers included medical records, medical, genetic, psychiatric and neuropsychological evaluations, brain MRI scan and EEG. Blood samples were analyzed for copy number variations, and deep sequencing of the affected 3q29 region was performed in patients and seven first‐degree relatives. Risk variants were identified through bioinformatic analysis. Results One deletion carrier was diagnosed with learning difficulties and childhood autism, the other with mild intellectual disability and schizophrenia. EEG abnormalities in childhood normalized in adulthood in both. Cognitive abilities improved during adolescence in one deletion carrier. Both had microcytic, hypochromic erythrocytes and suffered from chronic pain and fatigue. Molecular and bioinformatic analyses identified risk variants in the hemizygous allele that were not present in the homozygous state in relatives in genes involved in cilia function and insulin action in the autistic individual and in synaptic function and neurosteroid transport in the subject with schizophrenia. Conclusion 3q29 deletion carriers may undergo developmental phenotypic transition and need regular medical follow‐up. Identified risk variants in the remaining hemizygous allele should be explored further in autism and schizophrenia research.

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Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Cited by 7 publications

References 88 publications

Short- and long-term effects of radiation exposure at low dose and low dose rate in normal human VH10 fibroblasts

Short- and long-term effects of radiation exposure at low dose and low dose rate in normal human VH10 fibroblasts

Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

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