ABSTRACT 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.

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

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Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS IQSEC2 MUTATION ASSOCIATED WITH EPILEPSY, INTELLECTUAL DISABILITY, AND AUTISM RESULTS IN HYPEREXCITABILITY OF

PATIENT-DERIVED NEURONS AND DEFICIENT SYNAPTIC TRANSMISSION Article Open access 17 September 2021 _MINPP1_ PREVENTS INTRACELLULAR ACCUMULATION OF THE CHELATOR INOSITOL HEXAKISPHOSPHATE AND

IS MUTATED IN PONTOCEREBELLAR HYPOPLASIA Article Open access 30 November 2020 _CUL4B_ MUTATIONS IMPAIR HUMAN CORTICAL NEUROGENESIS THROUGH PP2A-DEPENDENT INHIBITION OF AKT AND ERK Article

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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. AUTHOR INFORMATION Author notes * These authors contributed equally: Renata Santos, Fred H. Gage, Mayana Zatz AUTHORS AND AFFILIATIONS * Human Genome and Stem

Cell Research Center, Biosciences Institute, University of São Paulo, 106 Rua do Matão, 05508-090, São Paulo, Brazil Thalita Figueiredo, Danielle P. Moreira, Ernesto Goulart, Danyllo

Oliveira, Gerson S. Kobayashi, Fernando Kok & Mayana Zatz * Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

Thalita Figueiredo, Ana P. D. Mendes, Shani Stern, Maria C. Marchetto, Renata Santos & Fred H. Gage * Faculty of Medicine, Federal University of Alagoas, Tabuleiro do Martins, 57072-900,

Maceió, Brazil Thalita Figueiredo * Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, 3498838, Israel Shani Stern * University of Paris, Institute

of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Dynamics of Neuronal Structure in Health and Disease, 102 rue de la Santé, 75014, Paris, France Renata Santos

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ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to

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Moreira, D.P. _et al._ Inositol monophosphatase 1 (_IMPA1_) mutation in intellectual disability patients impairs neurogenesis but not gliogenesis. _Mol Psychiatry_ 26, 3558–3571 (2021).

https://doi.org/10.1038/s41380-020-00862-9 Download citation * Received: 23 July 2019 * Revised: 27 July 2020 * Accepted: 30 July 2020 * Published: 24 August 2020 * Issue Date: July 2021 *

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