RSK2 enzymatic assay as a second level diagnostic tool in Coffin-Lowry syndrome.
BACKGROUND
Coffin-Lowry syndrome is a semi-dominant condition characterized by severe psychomotor retardation with facial, hand and skeletal malformations resulting from mutations in RSK2 gene, encoding for a serine/threonine kinase. More than 100 different mutations have been identified to date; however, about 50% of clinically diagnosed patients apparently do not have mutations. In order to exclude that these patients have RSK2 mutations missed by standard mutation detection techniques, a rapid and sensitive assay allowing evaluation of RSK2 activity was needed.


METHODS
RSK2 capacity to phosphorylate a synthetic CREB-peptide in basal and PMA-stimulated conditions was evaluated in lymphoblasts from 3 patients with RSK2 mutations and normal controls.


RESULTS
Patients RSK2 activity is normal in nonstimulated conditions but fails to grow following stimulation. The evaluation of the stimulated/non-stimulated activity ratio demonstrated a statistically significant impairment in patients.


CONCLUSIONS
We have set up an assay which allows the identification of even partial alterations of RSK2 activity and seems to give good results also in females with a balanced X-chromosome inactivation and thus with a presumably normal enzymatic activity in about 50% of cells. Moreover, our data seem to confirm previous reports of a potential direct correlation between the level of RSK2 activity and the severity of cognitive impairment.
Micheli
Vanna
V
Biological Chemistry, Department of Molecular Biology, University of Siena, Siena, Italy.
Sestini
Sylvia
S
Parri
Veronica
V
Fichera
Marco
M
Romano
Corrado
C
Ariani
Francesca
F
Longo
Ilaria
I
Mari
Francesca
F
Bruttini
Mirella
M
Renieri
Alessandra
A
Meloni
Ilaria
I
D000328:Adult; D001681:Biological Assay; D038921:Coffin-Lowry Syndrome / Q000175:diagnosis*; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry*
D017362:Cyclic AMP Response Element-Binding Protein; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3