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.

Researchers found changes in a gene called PPP1R3F that cause a new condition affecting brain development. This X-linked condition (passed from mothers to sons) causes developmental delays, mild intellectual disability, autism-like behaviors, seizures, and movement problems. The gene helps brain cells manage energy storage, and when it doesn't work properly, it affects how the brain develops and functions.

This study identified hemizygous variants in the PPP1R3F gene associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. The condition is characterized by developmental delay, mild intellectual disability, autism spectrum disorder features, seizures, and neurological abnormalities including tone, gait, and cerebellar issues. PPP1R3F is predominantly expressed in brain astrocytes and functions in glycogen metabolism regulation. Functional studies on nine variants revealed defects in protein binding, stability, localization, and glycogen metabolism.

The research suggests this represents a new X-linked disorder of glycogen metabolism, highlighting the critical role of protein phosphatase 1 regulatory subunits in neurological development.

Expands genetic testing panels for X-linked neurodevelopmental disorders. Establishes new diagnostic category linking glycogen metabolism to autism spectrum features. May inform targeted therapeutic approaches focusing on metabolic pathways. Important for genetic counseling of families with X-linked inheritance patterns.

Small sample size of 13 individuals limits generalizability. Study type not specified, suggesting potential limitations in methodology. Functional studies limited to nine of the identified variants. Long-term outcomes and treatment responses not evaluated.

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.