Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome.
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.
Trivier
E
E
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS,INSERM, Illkirch, France.
De Cesare
D
D
Jacquot
S
S
Pannetier
S
S
Zackai
E
E
Young
I
I
Mandel
J L
JL
Sassone-Corsi
P
P
Hanauer
A
A
D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002874:Chromosome Mapping; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D038601:Ribosomal Protein S6; D019893:Ribosomal Protein S6 Kinases; D012269:Ribosomal Proteins / Q000378:metabolism; D012729:Sex Chromosome Aberrations / Q000201:enzymology / Q000235:genetics*; D015398:Signal Transduction; D014960:X Chromosome
D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases