A CRISPR-Cas9–engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions
| Autor: | Lars Wittler, Marion Rivalan, Julika Pitsch, Peter N. Robinson, Albert J. Becker, Melissa Long, Despina Tsortouktzidis, Anne Voigt, Björn Fischer-Zirnsak, Stefan Mundlos, Guido Vogt, Peter Krawitz, York Winter, Uwe Kornak, Dietmar Schmitz, Karl Schilling, Alexej Knaus, Miguel Rodriguez de los Santos, Laura Moreno Velasquez, Denise Horn, Bernd Timmermann, Daniele Mattei, Alexander Stumpf, Friederike S. David |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
GPI-anchor deficiency
Glycosylphosphatidylinositols Mutation Missense Hippocampal formation Neurotransmission Biology Protein Engineering Hippocampus Mannosyltransferases 03 medical and health sciences Mice 0302 clinical medicine Germline mutation Seizures Intellectual Disability Gene expression disease modeling medicine Ephrin Missense mutation Animals Abnormalities Multiple Amino Acid Sequence Amino Acids hippocampal synaptic defect Gene 030304 developmental biology 0303 health sciences Multidisciplinary Epilepsy Microglia Biological Sciences Phenotype Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Mutation Synaptophysin biology.protein Signal transduction CRISPR-Cas Systems Function and Dysfunction of the Nervous System Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Inherited GPI-anchor biosynthesis deficiencies (IGDs) explain many cases of syndromic intellectual disability. Although diagnostic methods are improving, the pathophysiology underlying the disease remains unclear. Furthermore, we lack rodent models suitable for characterizing cognitive and social disabilities. To address this issue, we generated a viable mouse model for an IGD that mirrors the condition in human patients with a behavioral phenotype and susceptibility to epilepsy. Using this model, we obtained neurological insights such as deficits in synaptic transmission that will facilitate understanding of the pathophysiology of IGDs. 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. |
| Databáze: | OpenAIRE |
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