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  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., et al. (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): e2014481118. doi:10.1073/pnas.2014481118.

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 Creators:
de Los Santos, Miguel Rodríguez , Author
Rivalan, Marion , Author
David, Friederike S. , Author
Stumpf, Alexander , Author
Pitsch, Julika, Author
Tsortouktzidis, Despina , Author
Moreno Velasquez, Laura, Author
Voigt, Anne, Author
Schilling, Karl, Author
Mattei, Daniele , Author
Long, Melissa , Author
Vogt, Guido, Author
Knaus, Alexej, Author
Fischer-Zirnsak, Björn , Author
Wittler, Lars1, Author              
Timmermann, Bernd2, Author              
Robinson , Peter N. , Author
Horn, Denise, Author
Mundlos, Stefan3, Author              
Kornak, Uwe3, Author              
Becker, Albert J., AuthorSchmitz , Dietmar , AuthorWinter, York, AuthorKrawitz, Peter M. , Author more..
Affiliations:
1Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: GPI-anchor deficiency; disease modeling; hippocampal synaptic defect
 Abstract: 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 Pigv 341E 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 Pigv 341E mice, and electrophysiology recordings showed decreased hippocampal synaptic transmission that could underlie impaired memory formation. In single-cell RNA sequencing, Pigv 341E-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.

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Language(s): eng - English
 Dates: 2021-01-052021-01-12
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1073/pnas.2014481118
 Degree: -

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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : PNAS
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 118 (2) Sequence Number: e2014481118 Start / End Page: - Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230