Mutations in the Kinase Rsk-2 Associated With Coffin-Lowry Syndrome

Nature. 1996 Dec 12;384(6609):567-70. doi: 10.1038/384567a0.

Abstract

The Coffin-Lowry syndrome (CLS), an X-linked disorder, is characterized by severe psychomotor retardation, facial and digital dysmorphisms, and progressive skeletal deformations. Genetic linkage analysis mapped the CLS locus to an interval of 2-3 megabases at Xp22.2. The gene coding for Rsk-2, a member of the growth-factor-regulated protein kinases, maps within the candidate interval, and was tested as a candidate gene for CLS. Initial screening for mutations in the gene for Rsk-2 in 76 unrelated CLS patients revealed one intragenic deletion, a nonsense, two splice site, and two missense mutations. The two missenses affect sites critical for the function of Rsk-2. The mutated Rsk-2 proteins were found to be inactive in a S6 kinase assay. These findings provide direct evidence that abnormalities in the MAPK/RSK signalling pathway cause Coffin-Lowry syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / enzymology
  • Abnormalities, Multiple / genetics*
  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Chromosome Mapping
  • Female
  • Frameshift Mutation
  • Humans
  • Intellectual Disability / enzymology
  • Intellectual Disability / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Phosphorylation
  • Point Mutation
  • Polymorphism, Single-Stranded Conformational
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Ribosomal Protein S6
  • Ribosomal Protein S6 Kinases
  • Ribosomal Proteins / metabolism
  • Sex Chromosome Aberrations / enzymology
  • Sex Chromosome Aberrations / genetics*
  • Signal Transduction
  • X Chromosome*

Substances

  • Ribosomal Protein S6
  • Ribosomal Proteins
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases