Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• RSK2 (RPS6KA3) is a kinase in the Ras-MAPK pathway.
• Mutations in RSK2 cause Coffin-Lowry syndrome (CLS), an X-linked disorder.
• CLS presents with psychomotor retardation, facial/digital abnormalities, and skeletal deformities.

Purpose of the Study:

• To identify and characterize RSK2 gene mutations in patients with Coffin-Lowry syndrome.
• To investigate the correlation between mutation type, distribution, and clinical phenotype.

Main Methods:

• Screening of 250 patients with CLS-suggestive features.
• Genetic analysis to identify RSK2 mutations.
• In silico prediction of mutation effects on protein function.

Main Results:

• 71 distinct RSK2 mutations were identified in 86 unrelated families.
• 38% missense, 20% nonsense, 18% splicing, 21% indels.
• 57% of mutations cause premature termination, likely loss-of-function.
• Mutations are distributed throughout the gene with no clear clustering.
• Some missense mutations correlate with milder phenotypes, including in female patients.

Conclusions:

• RSK2 mutations are diverse and frequently lead to loss of function.
• Mutation type and distribution do not strongly correlate with CLS phenotype.
• Milder phenotypes, including in females, can be associated with specific missense mutations.