Overexpression of the 14-3-3gamma protein in embryonic mice results in neuronal migration delay in the developing cerebral cortex

Cornell, Brett; Wachi, Tomoka; Zhukarev, Vladimir; Toyo-oka, Kazuhito

doi:10.1016/j.neulet.2016.06.009

Cited by 17 publications

(26 citation statements)

References 24 publications

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“…41 Curiously, in mice, a decrease or increase in 14-3-3g leads to delayed neuronal migration of pyramidal neurons in the cerebral cortex. 42,43 Hence, normal neuronal migration in the developing brain is exquisitely sensitive to 14-3-3g levels. Atypical neuronal migration has previously been implicated in epilepsy.…”

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confidence: 99%

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Guella

McKenzie

Evans

et al. 2017

The American Journal of Human Genetics

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Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3g) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n ¼ 1) and YWHAG (n ¼ 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.

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confidence: 99%

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Guella

McKenzie

Evans

et al. 2017

The American Journal of Human Genetics

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“…The genes in the green boxes were duplicated using the MLPA P029 WBS probemix. brains when the YWHAG gene was knocked down, which reflects that a correct dose of the protein product of this gene is necessary for a normal brain development [Cornell et al, 2016]. Furthermore, the obesity seen in our patient may also be explained by the overexpression of this gene as was demonstrated by Capobianco et al [2012] because this gene is also involved in both cellular insulin-mediated glucose transport and lipid metabolism.…”

Section: Discussionmentioning

confidence: 52%

“…The duplication of YWHAG causes a delayed migration of pyramidal neurons to external layers of the cerebral cortex in different stages of brain development in mice. This is explained by a deficit in the locomotion stage of neuronal migration and not by an altered neurogenesis, which may reflect pathologic changes on microtubule dynamics [Cornell et al, 2016]. Importantly, this aberration was extremely similar to that seen in foetal mice Fig.…”

Section: Discussionmentioning

confidence: 52%

“…Concerning HIP1 , it has been demonstrated that its protein is overexpressed in brain cancers [Bradley et al, 2007], which may clarify why patient 2 developed a spinal cord schwannoma. Nevertheless, it is unclear how the HIP1 duplication can contribute to the neuropsychiatric phenotype, albeit the gene dose of this part of the 7q11.23 region may be significantly important for neural development [Cornell et al, 2016].…”

Section: Discussionmentioning

confidence: 99%

“…Although 4 patients with a duplication of HIP or HIP / YWHAG were also described by Ramocki et al [2010], which did not comprise the genes between LCR-P and LCR-C, there was no evidence of the relevance of the overexpression of these genes. However, Cornell et al [2016] recently provided strong evidence that the duplication of YWHAG causes neuronal migration delay in the developing cerebral cortex of mice, in a similar manner as YWHAG knockdown does. Here, we report the fifth patient with a distal 7q11.23 duplication (dup7q11.23D) and show the manifestations which could characterise this emerging microduplication syndrome.…”

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confidence: 99%

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Distal 7q11.23 Duplication, an Emerging Microduplication Syndrome: A Case Report and Further Characterisation

et al. 2016

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Chromosome 7q11.23 duplication syndrome is a well-recognised syndrome which involves the duplication of the same genes located in the Williams-Beuren critical region. However, in 2010, 4 patients were reported with a microduplication only in the HIP1 and YWHAG genes. We refer to this as a distal 7q11.23 duplication (dup7q11.23D). Here, we report the fifth de novo patient with dup7q11.23D, whose symptoms may be explained by YWHAG overexpression as was demonstrated recently in mice and obese patients. Finally, further studies will be necessary to delineate this emerging microduplication syndrome.

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Quantitative Proteomic Profiling of Cerebrospinal Fluid to Identify Candidate Biomarkers for Alzheimer's Disease

Sathe

Renuse

et al. 2019

Proteomics Clinical Apps

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Purpose Development of novel biomarkers for AD is important for early diagnosis, monitoring disease progression and therapeutic response. The aim of this study was to identify the potential CSF biomarkers for Alzheimer's disease (AD) and evaluate these markers on independent CSF samples using a parallel reaction monitoring mass spectrometry (PRM-MS) assay. Experimental design In this study, we employed high-resolution mass spectrometry and tandem mass tag (TMT) multiplexing technology to identify proteins that might serve as candidate biomarkers for Alzheimer’s disease. Identified potential biomarkers were validated using a parallel reaction monitoring mass spectrometry (PRM-MS) assay. Results We identified 2,327 proteins in the cerebrospinal fluid (CSF) of which 139 were observed to be significantly different in their abundance in the CSF of AD patients versus controls. The proteins whose abundance was altered in AD included a number of known AD marker proteins such as MAPT, NPTX2, SCG2, VGF, GFAP, SST and NCAM1 as well as novel biomarkers such as GSN, PKM and YWHAG. We then sought to validate these findings in a separate set of CSF specimens from AD dementia patients and controls. For the AD group, significant increases were found for YWHAG and PKM, and a significant decrease was observed for VGF by multiplexed targeted parallel reaction monitoring (PRM) experiments. NPTX2 in combination with PKM or with YWHAG led to the best results with AUCs of 0.935 and 0.933, respectively. Conclusions and clinical relevance The identified altered CSF proteins in AD CSF samples will be useful to understand AD pathogenesis.

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Overexpression of the 14-3-3gamma protein in embryonic mice results in neuronal migration delay in the developing cerebral cortex

Cited by 17 publications

References 24 publications

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Distal 7q11.23 Duplication, an Emerging Microduplication Syndrome: A Case Report and Further Characterisation

Quantitative Proteomic Profiling of Cerebrospinal Fluid to Identify Candidate Biomarkers for Alzheimer's Disease

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