MINPP1prevents intracellular accumulation of the cation chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia
Author:
Ucuncu Ekin, Rajamani Karthyayani, Wilson Miranda S.C., Medina-Cano Daniel, Altin Nami, David Pierre, Barcia Giulia, Lefort Nathalie, Vasilache-Dangles Marie-Thérèse, Pitelet Gaële, Lorino Elsa, Rabasse Nathalie, Bieth Eric, Zaki Maha S., Topcu Meral, Sonmez Fatma Mujgan, Musaev Damir, Stanley Valentina, Bole-Feysot Christine, Nitschké Patrick, Munnich Arnold, Bahi-Buisson Nadia, Fossoud Catherine, Giuliano Fabienne, Colleaux Laurence, Burglen Lydie, Gleeson Joseph G., Boddaert Nathalie, Saiardi Adolfo, 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 themultiple inositol polyphosphate phosphatase 1gene (MINPP1). Patients were found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We found that patient-derived and genome editedMINPP1-/-induced pluripotent stem cells (iPSCs) are not able to differentiate efficiently into neurons. 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 hexakiphosphate (IP6), detected in HEK293, 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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