Afficher la couverture 'MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia | Ucuncu, Ekin' en grand format
/5

0 avis

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

Archive ouverte

Ucuncu, Ekin | Rajamani, Karthyayani | Wilson, Miranda | Medina-Cano, Daniel | Altin, Nami | David, Pierre | Barcia, Giulia | Lefort, Nathalie | Banal, Céline | Vasilache-Dangles, Marie-Thérèse | Pitelet, Gaële | Lorino, Elsa | Rabasse, Nathalie | Bieth, Eric | Zaki, Maha | 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 | Boddaert, Nathalie | Saiardi, Adolfo | Cantagrel, Vincent

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

Suggestions

Du même auteur

De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Archive ouverte | Chemin, Jean | CCSD

IF 10.848. International audience. Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset ce...

Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population

Archive ouverte | Megahed, Hisham | CCSD

International audience. AbstractBackgroundCerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are hig...

Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population

Archive ouverte | Megahed, Hisham | CCSD

International audience. Background: Cerebellar atrophy and developmental delay are commonly associated features in large numbers of genetic diseases that frequently also include epilepsy. These defects are highly he...

Chargement des enrichissements...