气候变化领域集成服务门户(CCPortal): A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions

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DOI	10.1073/pnas.2014481118
	A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions
	de los Santos M.R.; Rivalan M.; David F.S.; Stumpf A.; Pitsch J.; Tsortouktzidis D.; Velasquez L.M.; Voigt A.; Schilling K.; Mattei D.; Long M.; Vogt G.; Knaus A.; Fischer-Zirnsak B.; Wittler L.; Timmermann B.; Robinson P.N.; Horn D.; Mundlos S.; Kornak U.; Becker A.J.; Schmitz D.; Winter Y.; Krawitz P.M.
发表日期	2021
ISSN	00278424
卷号	118 期号:2
英文摘要	Pathogenic germline mutations in PIGV lead to glycosylphosphatidylinositol biosynthesis deficiency (GPIBD). Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol (GPI)-anchor pathway exhibit cognitive impairments, motor delay, and often epilepsy. Thus far, the pathophysiology underlying the disease remains unclear, and suitable rodent models that mirror all symptoms observed in human patients have not been available. Therefore, we used CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, Pigv:c.1022C > A (p.A341E), at a site that is conserved in mice. Mirroring the human pathology, mutant Pigv341E mice exhibited deficits in motor coordination, cognitive impairments, and alterations in sociability and sleep patterns, as well as increased seizure susceptibility. Furthermore, immunohistochemistry revealed reduced synaptophysin immunoreactivity in Pigv341E mice, and electrophysiology recordings showed decreased hippocampal synaptic transmission that could underlie impaired memory formation. In single-cell RNA sequencing, Pigv341E-hippocampal cells exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction in Abl1 transcript levels in several cell clusters suggested a link to the signaling pathway of GPI-anchored ephrins. We also observed elevated levels of Hdc transcripts, which might affect histamine metabolism with consequences for circadian rhythm. This mouse model will not only open the doors to further investigation into the pathophysiology of GPIBD, but will also deepen our understanding of the role of GPI-anchor-related pathways in brain development. © This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Disease modeling; GPI-anchor deficiency; Hippocampal synaptic defect
语种	英语
scopus关键词	glycosylphosphatidylinositol anchored protein; histidine decarboxylase; RNA; single cell RNA; synaptophysin; Thy 1 membrane glycoprotein; unclassified drug; Abl1 gene; amplitude modulation; animal cell; animal experiment; animal model; Article; brain dysfunction; cell adhesion; cell subpopulation; clinical feature; cognitive defect; controlled study; CRISPR-CAS9 system; disease severity; embryo; excitatory postsynaptic potential; female; fibroblast; GABAergic system; gene; gene expression; genetic association; glycosylphosphatidylinositol anchor deficiency; Hdc gene; hippocampus; immunoreactivity; intellectual impairment; interneuron; long term memory; male; memory disorder; microglia; missense mutation; motor coordination; motor dysfunction; mouse; neuropathology; nonhuman; oligodendroglia; Pigv gene; post tetanic potentiation; priority journal; protein deficiency; protein expression; protein function; RNA sequencing; seizure; short term memory; sleep disorder; social behavior; spatial learning; spatial memory; synaptic transmission; working memory
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181082
作者单位	Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, 13353, Germany; Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, 13353, Germany; Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, 53127, Germany; Animal Outcome Core Facility of the NeuroCure Center, Charité-Universitätsmedizin Berlin, Berlin, 10117, Germany; Institute of Cognitive Neurobiology, Humboldt University, Berlin, 10117, Germany; Institute of Human Genetics, Faculty of Medicine, University Hospital Bonn, Bonn, 53127, Germany; Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, 10117, Germany; Section for Translational Epilepsy Research, Department of Neuropathology, University Hospital Bonn, Bonn, 53127, Germany; Department of Epileptology, University Hospital Bonn, Bonn, 53127, Germany; Anatomis...
推荐引用方式 GB/T 7714	de los Santos M.R.,Rivalan M.,David F.S.,et al. A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions[J],2021,118(2).
APA	de los Santos M.R..,Rivalan M..,David F.S..,Stumpf A..,Pitsch J..,...&Krawitz P.M..(2021).A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions.Proceedings of the National Academy of Sciences of the United States of America,118(2).
MLA	de los Santos M.R.,et al."A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions".Proceedings of the National Academy of Sciences of the United States of America 118.2(2021).