A homozygous mutation in the inositol monophosphatase 1 (IMPA1) gene was recently identified in nine individuals with severe intellectual disability (ID) and disruptive behavior. These individuals belong to the same family from Northeastern Brazil, which has 28 consanguineous marriages and 59 genotyped family members. IMPA1 is responsible for the generation of free inositol from de novo biosynthesis and recycling from inositol polyphosphates and participates in the phosphatidylinositol signaling pathway. To understand the role of IMPA1 deficiency in ID, we generated induced pluripotent stem cells (iPSCs) from patients and neurotypical controls and differentiated these into hippocampal dentate gyrus-like neurons and astrocytes. IMPA1-deficient neuronal progenitor cells (NPCs) revealed substantial deficits in proliferation and neurogenic potential. At low passage NPCs (P1 to P3), we observed cell cycle arrest, apoptosis, progressive change to a glial morphology and reduction in neuronal differentiation. These observations were validated by rescuing the phenotype with myo-inositol supplemented media during differentiation of patient-derived iPSCs into neurons and by the reduction of neurogenic potential in control NPCs-expressing shIMPA1. Transcriptome analysis showed that NPCs and neurons derived from ID patients have extensive deregulation of gene expression affecting pathways necessary for neurogenesis and upregulation of gliogenic genes. IMPA1 deficiency did not affect cell cycle progression or survival in iPSCs and glial progenitor cells or astrocyte differentiation. Therefore, this study shows that the IMPA1 mutation specifically affects NPC survival and neuronal differentiation.
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Acknowledgements This manuscript is dedicated to the family involved in this study. This study was financially supported by the CEPID-FAPESP (2013/08028-1), INCT/FAPESP (2014/50931-3) and FAPESP (process number: 2019/18469-1, 2017/19877-0, and 2016/ 09618-5). This work was supported in part by the National Cancer Institute (grant no. P30 CA014195) and the National Institutes of Health (grant no. R01AG05651) and by the National Cooperative Reprogrammed Cell Research Groups (NCRCRG) (grant no. U19 MH106434). The Gage laboratory is supported in part by the Leona M. and Harry B. Helmsley Charitable Trust grant no. 2017-PG-MED001, the JPB Foundation, Annette C. Merle-Smith, and the Robert and Mary Jane Engman Foundation. We also thank the Salk core facilities. This work was supported in part by the Next Generation Sequencing Core (NGS) Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195, the Chapman Foundation and the Helmsley Charitable Trust.
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Molecular Biology