Molecular characteristics

The loss of function of the RPS6KC1 protein leads to a systemic disruption of protein synthesis, cellular signaling pathways, and lipid metabolism. The main molecular characteristics identified include:

•    Impaired Ribosomal Protein Synthesis:Although RPS6KC1 lacks direct kinase activity, its loss results in significantly diminished expression and phosphorylation of RPS6 (specifically p-RPS6 Ser235), a vital component of the 40S ribosomal subunit. This leads to a generalized decrease in ribosomal biogenesis and the downregulation of other translation regulators, such as RPS6KA3, RPS6KB1, and eIF2α.
•    Repression of the mTOR/PI3K Pathway:A hallmark of the disease is the marked repression of the mTOR (mammalian target of rapamycin) and PI3K (phosphatidylinositol 3-kinase) pathways. Because mTOR is a master regulator of cell growth and metabolism, its hypoactivity has been associated with intellectual disability and brain malformations.
•    Disrupted Endosomal Anchoring and Interactor Function: RPS6KC1 normally facilitates the transport and anchoring of its interactors, PRDX3 (a mitochondrial antioxidant) and SPHK1 (sphingosine kinase 1), to endosomes via its PX domain. Mutations in RPS6KC1 lead to the mislocalization and reduced levels of these proteins, triggering a "metabolic ripple effect" that affects membrane trafficking and cellular protection against oxidative stress.
•    Lipid Signaling and Homeostasis Imbalance:The disorder causes significant alterations in the levels of phosphoinositides (PI, PIP, PIP2, PIP3) and bioactive sphingoid bases like sphingosine and dihydrosphingosine. Furthermore, the master lipid regulators SREBP1 and SREBP2 are dysregulated; the lack of mTOR activity prevents the proper activation and nuclear transport of SREBP1, contributing to systemic lipid imbalances such as elevated cholesterol and triglycerides.
•    Mitochondrial Morphology Changes: Fibroblasts from affected individuals exhibit mitochondrial hyperfusion, characterized by an increase in mitochondrial area, volume, and sphericity, along with a decrease in the number of individual, disconnected mitochondria.
•    Defective Nonsense-Mediated Decay (NMD):The impairment of the ribosomal machinery appears to interfere with the NMD process. This defect allows faulty mRNA transcripts that contain premature stop codons to evade degradation, which may further contribute to the variation in protein and lipid defects observed in patients.