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.

TitleHemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.
Publication TypeJournal Article
Year of Publication2023
AuthorsLiu, Z, Xin, B, Smith, IN, Sency, V, Szekely, J, Alkelai, A, Shuldiner, A, Efthymiou, S, Rajabi, F, Coury, S, Brownstein, CA, Rudnik-Schöneborn, S, Bruel, A-L, Thevenon, J, Zeidler, S, Jayakar, P, Schmidt, A, Cremer, K, Engels, H, Peters, SO, Zaki, MS, Duan, R, Zhu, C, Xu, Y, Gao, C, Sepulveda-Morales, T, Maroofian, R, Alkhawaja, IA, Khawaja, M, Alhalasah, H, Houlden, H, Madden, JA, Turchetti, V, Marafi, D, Agrawal, PB, Schatz, U, Rotenberg, A, Rotenberg, J, Mancini, GMS, Bakhtiari, S, Kruer, M, Thiffault, I, Hirsch, S, Hempel, M, Stühn, LG, Haack, TB, Posey, JE, Lupski, JR, Lee, H, Sarn, NB, Eng, C, Gonzaga-Jauregui, C, Zhang, B, Wang, H
JournalHum Mol Genet
Volume32
Issue20
Pagination2981-2995
Date Published2023 Oct 04
ISSN1460-2083
KeywordsAutism Spectrum Disorder, Autistic Disorder, Glucose, Glycogen, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Protein Phosphatase 1
Abstract

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.

DOI10.1093/hmg/ddad124
Alternate JournalHum Mol Genet
PubMed ID37531237
PubMed Central IDPMC10549786
Grant ListR01HL094505 / NH / NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
R01 NS106298 / NS / NINDS NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
R01 HL094505 / HL / NHLBI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States

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