Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models

• Type of Material: Article
• Authors: Lenin C Kandasamy, University of Tsukuba; Mina Tsukamoto, University of Tsukuba; Vitaliy Banov, Laboratory for Behavioral Genetics, CBS, RIKEN; Sambuu Tsetsegee, University of Tsukuba; Yutaro Nagasawa, University of Tsukuba; Mitsuhiro Kato, Showa University; Naomichi Matsumoto, Yokohama City University; Junji Takeda, Osaka University; Shigeyoshi Itohara, Laboratory for Behavioral Genetics, CBS, RIKEN; Sonoko Ogawa, University of Tsukuba; Larry Young, Emory University; Qi Zhang, University of Tsukuba
• Language: English
• Date: 2021-02-19
• Publisher: OXFORD UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [e-mail]
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddab052
• Title of Journal or Parent Work: HUMAN MOLECULAR GENETICS
• Volume: 30
• Issue: 9
• Start Page: 758
• End Page: 770
• Grant/Funding Information: RIKEN Incentive Research Project (100226201701100443) to Q.Z; the Brain Science Project, Center for novel science initiatives, National Institutes Of Natural Sciences (BS291003) to Q.Z; the RIKEN Aging Project (10026-201701100263-340120) to Q.Z; the JSPS Kakenhi Grant-in-Aid for Young Scientists (17K18362) to Q.Z; the JSPS Kakenhi Grant-in-Aid for Challenging Research (19K21807) to Q.Z; the International Education and Research Laboratory Program of University of Tsukuba to L.J.Y.
• Keywords: FAMILY; Genetics & Heredity; EPILEPSY; ANCHORED PROTEINS; PIGA MUTATION; DISRUPTION; Life Sciences & Biomedicine; SYNDROME 2 MCAHS2; Science & Technology; GROWTH; GERMLINE MUTATION; Biochemistry & Molecular Biology; SPERM
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities.