RPS6KA3 – Coffin-Lowry Syndrome

RPS6KA3 (HGNC:10432) encodes the serine/threonine kinase RSK2, a downstream effector of ERK1/2 signaling. Pathogenic variants in RPS6KA3 cause Coffin-Lowry syndrome, an X-linked semidominant disorder characterized by moderate to severe intellectual disability, distinctive facial features, stimulus-induced drop episodes, and progressive skeletal malformations.

1. Clinical Validity

Extensive case series and family studies support a Definitive gene–disease association. Over 100 unrelated probands have been reported with loss-of-function and missense variants in RPS6KA3, with consistent segregation in multigenerational kindreds and concordant functional data ([PMID:9837815]; [PMID:11180593]).

2. Genetic Evidence

Inheritance is X-linked semidominant, with hemizygous males fully affected and heterozygous females variably manifesting the phenotype. Segregation analysis demonstrates pathogenic variants co-segregating with disease in >20 additional affected relatives. More than 100 unique RPS6KA3 variants have been described, including nonsense, frameshift, splice-site, and missense changes, all predicted to abolish kinase activity. A recurrent variant, c.898C>T (p.Arg300Ter), has been identified in multiple cohorts ([PMID:19888300]; [PMID:26043507]).

3. Functional Evidence

Loss of RSK2 protein and kinase activity has been demonstrated by Western blot and phosphotransferase assays in patient‐derived cells, confirming haploinsufficiency as the principal mechanism ([PMID:9832033]). Rsk2-knockout mice exhibit impaired spatial learning, altered exploratory behavior, and skeletal defects mirroring human CLS, providing in vivo corroboration ([PMID:17033934]).

4. Integration and Conclusion

Genetic and experimental data converge on RPS6KA3 haploinsufficiency leading to neural and skeletal phenotypes of Coffin-Lowry syndrome. The broad variant spectrum, robust segregation, and mechanistic studies fulfill ClinGen criteria for a Definitive association. RPS6KA3 sequencing and RSK2 activity assays are critical for accurate diagnosis, genetic counseling, and potential therapeutic targeting of downstream pathways.

Key Take-home: Pathogenic RPS6KA3 variants cause Coffin-Lowry syndrome via loss of RSK2 kinase activity, supporting definitive clinical utility of molecular testing and functional assays.

References

• American Journal of Human Genetics • 1998 • Mutation analysis of the RSK2 gene in Coffin-Lowry patients: extensive allelic heterogeneity and a high rate of de novo mutations PMID:9837815
• Human Mutation • 2001 • Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome. PMID:11180593
• Journal of Medical Genetics • 1998 • Rapid immunoblot and kinase assay tests for a syndromal form of X linked mental retardation: Coffin-Lowry syndrome. PMID:9832033
• Behavior Genetics • 2007 • Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior. PMID:17033934

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