A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation

Mérienne, Karine; Jacquot, Sylvie; Pannetier, Solange; Zeniou, Maria; Bankier, Agnes; Gécz, Jozef; Mandel, Jean‐Louis; Mulley, John C.; Sassone–Corsi, Paolo; Hanauer, André

doi:10.1038/8719

Cited by 139 publications

(116 citation statements)

References 14 publications

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“…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.…”

Section: Diagnosticmentioning

confidence: 99%

“…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.…”

Section: Molecular and Genetic Basis Of Clsmentioning

confidence: 99%

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Coffin–Lowry syndrome

et al. 2009

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Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, which is characterized in male patients by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological signs in the hand are useful aids in the diagnosis. CLS is caused by mutations in the RPS6KA3 gene located at Xp22.2, which encodes RSK2, a growth-factor-regulated protein kinase. RPS6KA3 mutations are extremely heterogeneous and lead to loss of phosphotransferase activity in the RSK2 kinase, most often because of premature termination of translation.

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Section: Diagnosticmentioning

confidence: 99%

Section: Molecular and Genetic Basis Of Clsmentioning

confidence: 99%

Coffin–Lowry syndrome

et al. 2009

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“…This gene, which is involved in cognitive function and brain development, 46,47 has been implicated in several forms of Xlinked mental retardation (XLMR) resulting from both duplications and mutations. [47][48][49][50][51] This suggests that dysregulation in the expression of this gene in either direction can have profound effects, and may explain our findings of both increased and decreased levels. AP1S2 has also been implicated in XLMR, [52][53][54] and behavioral effects resulting from mutations are theorized to be due to brain-specific defects in intracellular protein trafficking.…”

Section: Discussionmentioning

confidence: 56%

X chromosome and suicide

et al. 2009

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Suicide completion rates are significantly higher in males than females in most societies. Although gender differences in suicide rates have been partially explained by environmental and behavioral factors, it is possible that genetic factors, through differential expression between genders, may also help explain gender moderation of suicide risk. This study investigated X-linked genes in suicide completers using a two-step strategy. We first took advantage of the genetic structure of the French-Canadian population and genotyped 722 unrelated French-Canadian male subjects, of whom 333 were suicide completers and 389 were non-suicide controls, using a panel of 37 microsatellite markers spanning the entire X chromosome. Nine haplotype windows and several individual markers were associated with suicide. Significant results aggregated primarily in two regions, one in the long arm and another in the short arm of chromosome X, limited by markers DXS8051 and DXS8102, and DXS1001 and DXS8106, respectively. The second stage of the study investigated differential brain expression of genes mapping to associated regions in Brodmann areas 8/9, 11, 44 and 46, in an independent sample of suicide completers and controls. Six genes within these regions, Rho GTPase-activating protein 6, adaptor-related protein complex 1 sigma 2 subunit, glycoprotein M6B, ribosomal protein S6 kinase 90 kDa polypeptide 3, spermidine/spermine N(1)-acetyltransferase 1 and THO complex 2, were found to be differentially expressed in suicide completers.

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“…In one family (MRX19), a missense mutation was associated solely with mild mental retardation. 4 In a total of 44 families, for which samples were available from the mothers of the probands, 25 (57%) mutations arose de novo in the proband, a higher frequence than expected. Germinal mosaicism has been reported in some families.…”

Section: Mutationsmentioning

confidence: 99%

“…Furthermore, patients showing only mild psychomotor retardation and/or mild or moderate skeletal anomalies have been documented. 3,4 Heterozygote detection in most carrier females is possible based usually on the presence of soft fleshy hands with thick tapering fingers and slight obesity. Furthermore, a coarse face with prominent brow, hypertelorism and thick nasal tissues, can be present.…”

Section: Clinical Definitionmentioning

confidence: 99%

X-linked Coffin-Lowry syndrome (CLS, MIM 303600, RPS6KA3 gene, protein product known under various names: pp90rsk2, RSK2, ISPK, MAPKAP1)

et al. 2002

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The Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation characterised in male patients by psychomotor and growth retardation, and various skeletal anomalies. CLS is caused by mutations in a gene located in Xp22.2 and encoding RSK2, a growth-factor regulated protein kinase. Mutations are extremely heterogeneous and lead to premature termination of translation and/or to loss of phosphotransferase activity. No correlation between the type and location of mutation and the clinical phenotype is evident. However, in one family (MRX19), a missense mutation was associated solely with mild mental retardation and no other clinical feature. Screening for RSK2 mutations is essential in most cases to confirm the diagnosis as well as for genetic counseling.

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A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation

Cited by 139 publications

References 14 publications

Coffin–Lowry syndrome

Coffin–Lowry syndrome

X chromosome and suicide

X-linked Coffin-Lowry syndrome (CLS, MIM 303600, RPS6KA3 gene, protein product known under various names: pp90rsk2, RSK2, ISPK, MAPKAP1)

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