Planas-Serra, L., Rodríguez-Ruiz, M., Anderson, E.N., Rodríguez-Palmero, A., Vélez-Santamaria, V., Schlüter, A., Verdura, E., Gereñu, G., Jiménez-Zúñiga, A., Iñañez, A., Casas, J., Bech, J.J., De La Torre, C., Martínez, J.J., Ruiz, M., Fourcade, S., Iascone, M., Tenconi, R., Meier, K., Diegmann, S., Lee, R.H.C., Beland, B., Mir, A., Darvish, H., Chung, W., Karimiani, E.G., Leal, S.M., Schrauwen, I., Öhman, S., Järvelä, I., Granvik, J., Reinson, K., Kurvinen, E., Õunap, K., Schwan, A., Platzer, K., Kalayci, T., Sharifi, S., Korenke, G.C., Houlden, H., Maroofian, R., López de Munaín, A., Casasnovas, C., Pandey, U.B., Pujol, A. (2025). Bi-allelic variants in the ribosomal protein RPS6KC1 cause a complex neurodevelopmental disorder.  Am. J. Hum. Genet. 112(11): 2643--2664.

FBrf0263813

Research paper

The ribosomal protein S6 kinase family members play essential biological functions in disease, from cancer to intellectual disability. Little is known about ribosomal proteins S6 kinase C1 (RPS6KC1), aside from its lack of phosphorylation capacity and its roles in sphingosine-1-phosphate signaling and peroxiredoxin-3 (PRDX3) transport to mitochondria. Through whole-exome sequencing, we identified bi-allelic RPS6KC1 variants in 13 individuals from 8 independent families. Phenotypic manifestations included neurodevelopmental delay, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome caused by RPS6KA3 mutations. Functional studies on peripheral blood mononuclear cells (PBMCs) from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and sphingosine kinase 1 (SPHK1), accompanied by marked repression of the mammalian target of rapamycin (mTOR)/phosphatidylinositol 3-kinase (PI3K) pathway. We detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Further studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan. These findings underscore the crucial roles of RPS6KC1 in neurodevelopment by controlling ribosomal protein synthesis, lipid signaling, and the mTOR pathway.