Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.
PPP1R3F
X-linked
developmental delay
glycogen metabolism
intellectual disability
protein phosphatase 1
seizureautism
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
04 Oct 2023
04 Oct 2023
Historique:
received:
12
05
2023
revised:
20
07
2023
accepted:
26
07
2023
pmc-release:
02
08
2024
pubmed:
2
8
2023
medline:
2
8
2023
entrez:
2
8
2023
Statut:
ppublish
Résumé
Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.
Identifiants
pubmed: 37531237
pii: 7235668
doi: 10.1093/hmg/ddad124
pmc: PMC10549786
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2981-2995Subventions
Organisme : NIH HHS
ID : R01HL094505
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG011758
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL094505
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007526
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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