Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis

Okazaki, Taro; Saito, Yoshiaki; Ueda, Riyo; Awashima, Takeya; Nishimura, Yoko; Yuasa, Isao; Shinohara, Yuki; Adachi, Kaori; Sasaki, Masayuki; Nanba, Eiji; Maegaki, Yoshihiro

doi:10.1016/j.braindev.2016.07.004

Cited by 17 publications

(10 citation statements)

References 9 publications

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“…Allen Developing Mouse Brain Atlas. Available from: http://developingmouse.brain-map.org/) and FGFRs have been associated with neurodevelopmental diseases including schizophrenia (O'Donovan et al, 2009; Terwisscha van Scheltinga et al, 2013), epilepsy (Coci et al, 2017; Okazaki et al, 2017), autism spectrum disorders (Wentz et al, 2014; Coci et al, 2017) and lissencephaly (Tan and Mankad, 2018), suggesting possible roles in neuron migration. However, analysis of cortical neuron migration in FGFR mutant mice has been inconclusive for two reasons.…”

Section: Introductionmentioning

confidence: 99%

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration

Kon

Calvo-Jiménez

Cossard

et al. 2019

eLife

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The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linked polyubiquitination and lysosomal degradation. Accordingly, FGFRs accumulate and stimulate prolonged Erk1/2 phosphorylation. Neurons inhibited for Erk1/2 are stalled in the multipolar zone. Moreover, Reelin, a secreted protein regulating neuronal positioning, prevents FGFR degradation through N-Cadherin, causing Erk1/2 phosphorylation. These findings reveal novel functions for FGFRs in cortical projection neuron migration, suggest a physiological role for FGFR and N-Cadherin interaction in vivo and identify Reelin as an extracellular upstream regulator and Erk1/2 as downstream effectors of FGFRs during neuron migration.

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Section: Introductionmentioning

confidence: 99%

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration

Kon

Calvo-Jiménez

Cossard

et al. 2019

eLife

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“…This secreted proteoglycan that enhances FGF signaling is broadly expressed in brain 60 , and functions as an extracellular chaperone for locally stored FGFs in the ECM, thereby influencing glucose metabolism by regulating rate-limiting enzymes in gluconeogenesis 61 . Other potentially relevant genes displaying the same expression trend were the heparan sulphate proteoglycan GPC2 (a marker of immature neurons 62,63 ), the helix-loop-helix transcription factor ID4 (a marker of postmitotic neurons 64 ), and the signaling molecule FGFR3 that has been implicated in epilepsy 65 . Genes downregulated in KO cells and upregulated in rescue cells included urokinase-type plasminogen activator PLAU (deficiency in mouse models increases seizure susceptibility 66 ), the glycoprotein GALNT7 (upregulation of which has been found to promote glioma cell invasion 67 ) and the brain tumor gene MYBL1 (that has been shown to be regulated by O -linked N -acetylglucosamine 68 .…”

Section: Resultsmentioning

confidence: 99%

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Perenthaler

Nikoncuk

Yousefi

et al. 2019

Preprint

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2 52 Running title: Loss of UGP2 causes a severe epileptic encephalopathy 53 54 55 Abstract: 60 Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic 61 disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we 62 report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, 63 severe developmental delay, progressive microcephaly and visual disturbance. Whole exome 64 sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essential UDP-65 glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable 66Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start 67 codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction 68 of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated 69unfolded protein response and premature neuronal differentiation, as modelled during pluripotent 70 stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to 71 differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in 72 vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our 73 study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive 74 DEE. Importantly, it also shows that isoform specific start-loss mutations causing expression loss of a 75 tissue relevant isoform of an essential protein can cause a genetic disease, even when an organism-76 wide protein absence is incompatible with life. We provide additional examples where a similar 77 disease mechanism applies. 78 79 80 81 82 83 84 85 86 87 3 Introduction: 88 Developmental and/or epileptic encephalopathies (DEEs) are a heterogeneous group of genetic 89 disorders, characterized by severe epileptic seizures in combination with developmental delay or 90 regression 1 . Genes involved in multiple pathophysiological pathways have been implicated in DEEs, 91 including synaptic impairment, ion channel alterations, transporter defects and metabolic processes 92 such as disorders of glycosylation 2 . Mostly, dominant acting, de novo mutations have been identified 93 in children suffering from DEEs 3 , and only a limited number of genes with a recessive mode of 94 inheritance are known so far, with a higher occurrence rate in consanguineous populations 4 . A recent 95 cohort study on DEEs employing whole exome sequencing (WES) and copy-number analysis, 96however, found that up to 38% of diagnosed cases might be caused by recessive genes, indicating 97 that the importance of this mode of inheritance in DEEs has been underestimated 5 . 98

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“…The FGFR3 gene, encoding a member of the fibroblast growth factor receptor family, has been reported to be exclusively expressed in the locus coeruleus in patients with major depressive disorder [ 89 ]. Previous studies have demonstrated that skeletal dysplasia patients with Asn540Lys mutation in the FGFR3 gene have been documented to accompany with medial temporal lobe dysgenesis and epilepsy [ 90–92 ].…”

Section: Discussionmentioning

confidence: 99%

Integrative genomics analysis identifies five promising genes implicated in insomnia risk based on multiple omics datasets

Sun

Zhang²,

et al. 2020

Bioscience Reports

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In recent decades, many genome-wide association studies on insomnia have reported numerous genes harboring multiple risk variants. Nevertheless, the molecular functions of these risk variants conveying risk to insomnia are still ill-studied. In this study, we integrated GWAS summary statistics (N = 386,533) with two independent brain expression quantitative trait loci (eQTL) datasets (N = 329) to determine whether expression-associated SNPs convey risk to insomnia. Furthermore, we applied numerous bioinformatics analyses to highlight promising genes associated with insomnia risk. By using Sherlock integrative analysis, we detected 449 significant insomnia-associated genes in the discovery stage. These identified genes were significantly overrepresented in 6 biological pathways including Huntington’s disease (P = 5.58×10-5), Alzheimer’s disease (P = 5.58×10-5), Parkinson’s disease (P = 6.34×10-5), spliceosome (P = 1.17×10-4), oxidative phosphorylation (P = 1.09×10-4), and wnt signaling pathways (P = 2.07×10-4). Further, 5 of these identified genes were replicated in an independent brain eQTL dataset. Through a PPI network analysis, we found that there existed highly functional interactions among these 5 identified genes. 3 genes of LDHA (P = 0.044), DALRD3 (P = 5.0×10-5) and HEBP2 (P = 0.032) showed significantly lower expression in brain tissues of insomnic patients than that in controls. In addition, the expression levels of these 5 genes showed prominently dynamic changes across different time points between behavioral states of sleep and sleep deprivation in mice brain cortex. Together, this study strongly suggested that these 5 identified genes may represent candidate genes and contributed risk to the etiology of insomnia.

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Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis

Cited by 17 publications

References 9 publications

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Integrative genomics analysis identifies five promising genes implicated in insomnia risk based on multiple omics datasets

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