MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia
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Published:2020-11-30
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Ucuncu Ekin, Rajamani Karthyayani, Wilson Miranda S. C., Medina-Cano DanielORCID, Altin Nami, David Pierre, Barcia Giulia, Lefort Nathalie, Banal Céline, Vasilache-Dangles Marie-Thérèse, Pitelet Gaële, Lorino Elsa, Rabasse Nathalie, Bieth Eric, Zaki Maha S.ORCID, Topcu Meral, Sonmez Fatma Mujgan, Musaev Damir, Stanley Valentina, Bole-Feysot Christine, Nitschké PatrickORCID, Munnich Arnold, Bahi-Buisson Nadia, Fossoud Catherine, Giuliano Fabienne, Colleaux Laurence, Burglen LydieORCID, Gleeson Joseph G.ORCID, Boddaert Nathalie, Saiardi AdolfoORCID, Cantagrel VincentORCID
Abstract
AbstractInositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome editedMINPP1−/−induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.
Funder
Fondation pour la Recherche Médicale Fondation Bettencourt Schueller RCUK | Medical Research Council Agence Nationale de la Recherche MSDAvenir fund (DEVO-DECODE project) ASSOCIATION «CONNAITRE LES SYNDROMES CEREBELLEUX»
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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