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
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Research Support, Non-U.S. Gov't
MeSH terms
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Abnormalities, Multiple / enzymology
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Abnormalities, Multiple / genetics*
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Amino Acid Sequence
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Base Sequence
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Cell Line
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Chromosome Mapping
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Female
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Frameshift Mutation
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Humans
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Intellectual Disability / enzymology
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Intellectual Disability / genetics*
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Male
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Molecular Sequence Data
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Mutation*
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Phosphorylation
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Point Mutation
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Polymorphism, Single-Stranded Conformational
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Ribosomal Protein S6
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Ribosomal Protein S6 Kinases
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Ribosomal Proteins / metabolism
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Sex Chromosome Aberrations / enzymology
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Sex Chromosome Aberrations / genetics*
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Signal Transduction
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X Chromosome*
Substances
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Ribosomal Protein S6
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Ribosomal Proteins
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases