Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Ribosomal protein S6 kinase family members are crucial in disease.
• Ribosomal protein S6 kinase C1 (RPS6KC1) function is largely unknown, despite its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 (PRDX3) transport.

Purpose of the Study:

• To investigate the role of RPS6KC1 in human disease and cellular function.
• To identify the molecular mechanisms underlying RPS6KC1-associated neurodevelopmental disorders.

Main Methods:

• Whole-exome sequencing to identify RPS6KC1 variants in affected individuals.
• Functional studies using patient-derived cells (PBMCs) and cell lines (HAP1).
• In vivo studies using Drosophila melanogaster models.

Main Results:

• Bi-allelic RPS6KC1 variants were found in 13 individuals from 8 families, presenting with neurodevelopmental delay, hypotonia, spastic paraplegia, and white matter loss.
• RPS6KC1 deficiency led to reduced RPS6 phosphorylation, impaired ribosomal protein synthesis, decreased PRDX3 and sphingosine kinase 1 (SPHK1) interactors, and repressed mTOR/PI3K pathway activity.
• RPS6KC1 knockdown in cells suggested a role in endosome anchoring of PRDX3 and SPHK1; Drosophila models showed locomotor dysfunction, reduced lifespan, and decreased mTOR activity.

Conclusions:

• RPS6KC1 is essential for neurodevelopment, regulating ribosomal protein synthesis, lipid signaling, and the mTOR pathway.
• RPS6KC1 variants cause a spectrum of neurodevelopmental and neurological disorders.
• RPS6KC1's function in endosome anchoring and its impact on cellular pathways highlight its critical biological importance.