Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome

Abstract

An unreported missense mutation of the ribosomal S6 kinase 2 (RSK2) gene has been identified in two male sibs with a mild form of CoYn-Lowry syndrome (CLS) inherited from their healthy mother. They exhibit transient severe hypotonia, macrocephaly, delay in closure of the fontanelles, normal gait, and mild mental retardation, associated in the first sib with transient autistic behaviour. Some dysmorphic features of CLS (in particular forearm fullness and tapering fingers) and many atypical findings (some of which were reminiscent of FG syndrome) were observed as well. The moderate phenotypic expression of this mutation extends the CLS phenotype to include less severe mental retardation and minor, hitherto unreported signs. The missense mutation identified may be less deleterious than those previously described. As this mutation occurs in a protein domain with no predicted function, it could be responsible for a conformational change aVecting the protein catalytic function, since a non-polar amino acid is replaced by a charged residue. (J Med Genet 1999;36:775-778)

Coffin–Lowry syndrome

“…Two additional families with atypical cases of the disease have also been documented. 5,6 This suggests that RSK2 mutations not producing the classical phenotype are a rare, but not insignificant, cause of nonsyndromic X-linked mental retardation, and that strict reliance on characteristic dysmorphic features may result in a missed diagnosis.…”

“…In addition, a few missense mutations leading to partial abolition of RSK2 phosphotransferase activity of the mutant protein were associated with very mild phenotypes, suggesting a role of residual activity in determining the severity of the syndrome. [5][6][7] Figure 1 (a-d) Facial views of a boy with CLS at different ages showing evolution during infancy of facial gestalt. (a) At 9 months, (b) at 18 months, (c) at 3 years, and (d) at 6 years.…”

Identification of Novel Mutations in Patients with Coffin–Lowry Syndrome by a Denaturing HPLC-Based Assay

“…These mutations were not observed in other healthy relatives of these patients. It is likely that these alterations, as already reported for other RSK2 missense mutations (11,12 ), do not entirely impair the protein function.…”

Genetic effects on human cognition: lessons from the study of mental retardation syndromes

“…Exons 1-22 are drawn as boxes (not to scale). Numbers above exons refer to the number of mutations described by Jacquot et al 37 dendrites perform computational tasks, 55 transforming presynaptic inputs into a signal delivered to the cell's axon. The relative computational autonomy of dendrites goes along with another discovery, that they control local protein production, critical for the development of long lasting synaptic change and a putative molecular substrate of learning and memory.…”