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A CRISPR-Cas9-engineered mouse model for GPI anchor deficiency mirrors human phenotype and shows hippocampal synaptic dysfunctions

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Title:A CRISPR-Cas9-engineered mouse model for GPI anchor deficiency mirrors human phenotype and shows hippocampal synaptic dysfunctions
Creators Name:Rodríguez de los Santos, M. and Rivalan, M. and David, F.S. and Knaus, A. and Stumpf, A. and Velasquez, L.M. and Voigt, A. and Mattei, D. and Long, M. and Vogt, G. and Wittler, L. and Timmermann, B. and Robinson, P.N. and Horn, D. and Mundlos, S. and Kornak, U. and Schmitz, D. and Winter, Y. and Krawitz, P.M.
Abstract:Pathogenic germline mutations in PIGV lead to glycosylphosphatidylinositol biosynthesis deficiency. Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol anchor pathway show cognitive impairments, a motor delay and in many cases epilepsy. Thus far, the pathophysiology underlying the disease remains unclear and suitable rodent models that mirror human pathophysiology have not been available. We therefore generated a mouse model using CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, at a site that is also conserved in mice, Pigv:c.1022C>A (p.A341E). Reflecting the human pathology mutant Pigv(341E) mice showed deficits in motor coordination and cognitive impairment with poorer long-term spatial memory than wild-type mice, as well as alterations in sociability and sleep patterns. Furthermore, immunohistochemistry showed decreased synaptophysin-immunoreactivity and electrophysiology recordings demonstrated reduced hippocampal synaptic transmission in Pigv(341E) mice that may underlie impaired memory formation. To gain a deeper and broader molecular understanding of the consequences of glycosylphosphatidylinositol anchor deficiency, we performed single-cell RNA sequencing on acutely isolated hippocampal cells of Pigv(341E) and wild-type mice. We found that hippocampal cells from adult Pigv(341E) mice exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction of Abl1 transcripts in several cell clusters suggests a link to the signaling pathway of glycosylphosphatidylinositol-anchored ephrins. We also observed increased levels of Hdc that might affect histamine metabolism with consequences in circadian rhythm. In summary, we present here the first mouse model with a patient-specific hypomorphic mutation that mirrors the human phenotype and shows a hippocampal synaptic defect. This new mouse model will not only open the doors for further investigation into the pathophysiology of glycosylphosphatidylinositol biosynthesis deficiency in future studies, but will also deepen our understanding in the role of glycosylphosphatidylinositol-anchor related pathways in brain development.
Keywords:GPI Anchor Deficiency, Disease Modelling, Hippocampal Synaptic Defect, Animals, Mice
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.04.20.050591
Date:21 April 2020
Official Publication:https://doi.org/10.1101/2020.04.20.050591

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