2. Academic Validation
  3. MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

  • Nat Commun. 2020 Nov 30;11(1):6087. doi: 10.1038/s41467-020-19919-y.
Ekin Ucuncu 1,  Karthyayani Rajamani 1,  Miranda S C Wilson 2,  Daniel Medina-Cano 1,  Nami Altin 1,  Pierre David 3,  Giulia Barcia 1 4,  Nathalie Lefort 5,  Céline Banal 5,  Marie-Thérèse Vasilache-Dangles 6,  Gaële Pitelet 7,  Elsa Lorino 8,  Nathalie Rabasse 9,  Eric Bieth 10,  Maha S Zaki 11,  Meral Topcu 12,  Fatma Mujgan Sonmez 13 14,  Damir Musaev 15,  Valentina Stanley 15,  Christine Bole-Feysot 16,  Patrick Nitschké 17,  Arnold Munnich 18,  Nadia Bahi-Buisson 19,  Catherine Fossoud 20,  Fabienne Giuliano 21,  Laurence Colleaux 1,  Lydie Burglen 1 22,  Joseph G Gleeson 15,  Nathalie Boddaert 23,  Adolfo Saiardi 24,  Vincent Cantagrel 25
Affiliations

Affiliations

  • 1 Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France.
  • 2 MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT, London, UK.
  • 3 Transgenesis Platform, Laboratoire d'Expérimentation Animale et Transgenèse (LEAT), Imagine Institute, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, 75015, Paris, France.
  • 4 Département de Génétique Médicale, AP-HP, Hôpital Necker-Enfants Malades, F-75015, Paris, France.
  • 5 Université de Paris, iPSC Core Facility, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France.
  • 6 Département de Neurologie Pédiatrique, AP-HP, Hôpital Necker-Enfants Malades, F-75015, Paris, France.
  • 7 Service de Neuropédiatrie, CHU Nice, 06200, Nice, France.
  • 8 ESEAN, 44200 Nantes, Service de maladies chroniques de l'enfant, CHU Nantes, 44093, Nantes, France.
  • 9 Service de pédiatrie, hôpital d'Antibes-Juan-les-Pins, 06600, Antibes-Juan-les-Pins, France.
  • 10 Service de Génétique Médicale, CHU Toulouse, 31059, Toulouse, France.
  • 11 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, 12311, Egypt.
  • 12 Department of Child Neurology, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey.
  • 13 Guven Hospital, Child Neurology Department, Ankara, Turkey.
  • 14 Department of Child Neurology, Faculty of Medicine, Karadeniz Technical University, Trabzon, 61080, Turkey.
  • 15 Laboratory for Pediatric Brain Diseases, Rady Children's Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • 16 Université de Paris, Genomics Platform, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France.
  • 17 Université de Paris, Bioinformatics Core Facility, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France.
  • 18 Université de Paris, Translational Genetics Laboratory, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France.
  • 19 Université de Paris, Genetics and Development of the Cerebral Cortex Laboratory, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France.
  • 20 Centre de Référence des Troubles des Apprentissages, Hôpitaux Pédiatriques de Nice CHU-Lenval, 06200, Nice, France.
  • 21 Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice, 06202, Nice, France.
  • 22 Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, 75012, Paris, France.
  • 23 Département de radiologie pédiatrique, INSERM UMR 1163 and INSERM U1000, AP-HP, Hôpital Necker-Enfants Malades, F-75015, Paris, France.
  • 24 MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT, London, UK. [email protected].
  • 25 Université de Paris, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, F-75015, Paris, France. [email protected].
PMID: 33257696 DOI: 10.1038/s41467-020-19919-y
Abstract

Inositol 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 edited MINPP1-/- 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 IP6 level 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.

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