Alternative titles; symbols
HGNC Approved Gene Symbol: RPS6KA3
SNOMEDCT: 15182000;
Cytogenetic location: Xp22.12 Genomic coordinates (GRCh38): X:20,149,911-20,267,097 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.12 | Coffin-Lowry syndrome | 303600 | X-linked dominant | 3 |
| Intellectual developmental disorder, X-linked 19 | 300844 | X-linked dominant | 3 |
The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase) family of growth factor-regulated serine/threonine kinases, known also as p90(rsk). RSK proteins contain 2 functional kinase catalytic domains: the N-terminal kinase domain belongs to the AGC kinase family (see 188830), and the C-terminal kinase domain belongs to the CamK family (see 604998). The kinase domains are connected by a 100-amino acid linker region containing a PDK (PDPK1; 605213) docking site. RSK proteins are directly phosphorylated and activated by MAPK proteins (e.g., ERK1; 601795) in response to growth factors, polypeptide hormones, and neurotransmitters, and then subsequently phosphorylate many substrates. RSKs appear to have important roles in cell cycle progression, differentiation, and cell survival (review by Marques Pereira et al., 2010).
Bjorbaek et al. (1995) showed that the cDNA encoding RPS6KA3, which they called ISPK1, encodes a predicted protein of 740 amino acids.
Zeniou et al. (2002) determined the expression of the RSK1 (RPS6KA1; 601684), RSK2, and RSK3 (RPS6KA2; 601685) genes in various human tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue-specific variations in levels suggested that the proteins may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus, and Purkinje cells. The authors suggested that in these areas, which are essential to cognitive function and learning, the RSK1 and RSK3 genes may not be able to fully compensate for a lack of RSK2 function.
Jacquot et al. (1998) found that the open reading frame of the RPS6KA3 coding region contains 22 exons.
In a study of the region of the X chromosome (Xp22.2) within which the Coffin-Lowry syndrome (CLS; 303600) maps, Trivier et al. (1996) identified an expressed sequence tag (EST) that showed 100% homology with a cDNA coding for RPS6KA3. Its localization was independently confirmed by Bjorbaek et al. (1995).
During the immediate-early response of mammalian cells to mitogens, histone H3 (see 602810) is rapidly and transiently phosphorylated by one or more kinases. Sassone-Corsi et al. (1999) demonstrated that RSK2 was required for epidermal growth factor (EGF; 131530)-stimulated phosphorylation of H3. Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wildtype RSK2 gene restored EGF-stimulated phosphorylation of H3 in the CLS cells. In addition, disruption of the RSK2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of RSK2, suggesting to Sassone-Corsi et al. (1999) that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression.
Thomas et al. (2005) presented evidence suggesting that RSK2 is involved in regulation of excitatory AMPA receptor synaptic transmission by interacting with and phosphorylating PDZ domain-containing proteins.
Spindle assembly checkpoint (SAC) prevents anaphase onset until all chromosomes have successfully attached to spindle microtubules. Using Xenopus egg extracts and HeLa cells, Vigneron et al. (2010) found that RSK2 had a role in spindle assembly checkpoint. RSK2 localized to kinetochores during SAC. Immunofluorescence analysis and knockdown studies revealed that RSK2 and Aurora B (AURKB; 604970) depended upon each other for kinetochore localization. Association of RSK2 at kinetochores was required to maintain SAC activation and localization of MAD1 (MXD1; 600021), MAD2 (MAD2L1; 601467), and CENPE (117143) at kinetochores. Expression of Xenopus Rsk2 rescued the effects of RSK2 knockdown in HeLa cells.
Zhou et al. (2013) found that ILKAP (618909) interacted with RSK2 in the nucleus and inhibited its activity. Inhibition of RSK2 kinase activity induced apoptosis by reducing expression of the RSK2 downstream factor cyclin D1 (CCND1; 168461).
Coffin-Lowry Syndrome
The localization of the RSK2 gene within the Coffin-Lowry syndrome (CLS; 303600) interval, together with its role in signaling pathways, prompted Trivier et al. (1996) to investigate its possible implication in CLS. Patient samples from 76 families were screened, and 1 patient was found to have a genomic deletion of approximately 2 kb. Amplification by RT-PCR of cDNA from the patient and direct sequencing showed a deletion of 187 bp between nucleotide positions 406 and 593 (300075.0001). The deletion produced a frameshift, generating a TAA termination codon 33 bp downstream of the deletion junction. The mutation cosegregated with CLS in 2 affected males and 1 female with discrete manifestations in this family. Trivier et al. (1996) then searched for point mutations and found both nonsense and missense mutations. Tissue-specific differences in gene expression suggested distinct physiologic roles for the various members of the RSK family (Moller et al., 1994; Zhao et al., 1995). RSK3 differs with respect to substrate specificity from other RSKs and may also have distinct upstream activators. Trivier et al. (1996) noted that in CLS, RSK1 and RSK3 are expressed at levels equivalent to those in normal individuals, indicating that they are not capable of overcoming the RSK2 deficiency. However, no abnormality of glycogen metabolism was found in CLS patients, although RSK2 was shown to be responsible for the activation of glycogen synthesis (Dent et al., 1990).
Jacquot et al. (1998) designed primers for PCR amplification of single exons from genomic DNA and subsequent SSCP analysis. They screened 37 patients with clinical features suggestive of CLS; 25 nucleotide changes predicted to be disease-causing mutations were identified, including 8 splice site alterations, 7 nonsense mutations, 5 frameshift mutations, and 5 missense mutations. Of the 25 mutations, 23 were novel. Coupled with previously reported mutations, these findings brought the total of different RSK2 mutations to 34. These were distributed throughout the RSK2 gene, with no clustering, and all but 2, which were found in 2 independent patients, were unique. A very high (68%) rate of de novo mutations was observed. Three mutations were found in female probands with no affected male relatives; these patients were ascertained through learning disability and mild but suggestive facial and digital dysmorphisms. No obvious correlation was observed between the position or type of the RSK2 mutations and the severity or particular clinical features of CLS.
Abidi et al. (1999) tested 5 unrelated individuals with CLS for mutations in 9 exons of the RSK2 gene using SSCP analysis. Two patients had the same missense mutation, 340C-T, predicted to cause an arg114-to-trp amino acid change (300075.0006). This mutation falls just outside the N-terminal ATP-binding site in a highly conserved region of the protein and may lead to structural changes since tryptophan has an aromatic side chain whereas arginine is a 5-carbon basic amino acid. The third patient had a 2186G-A nucleotide change, resulting in an arg729-to-gln missense mutation (300075.0009). The fourth patient had a 2-bp deletion (AG) of bases 451 and 452 (300075.0007). This created a frameshift that resulted in a stop codon 25 amino acids downstream, thereby producing a truncated protein. This deletion also falls within the highly conserved amino-catalytic domain of the protein. The fifth patient had a 2065C-T nucleotide change that resulted in a premature stop codon, thereby producing a truncated protein (300075.0008). Three of the patients in whom RSK2 mutations were identified by Abidi et al. (1999) had at least 1 brother who also carried the diagnosis of CLS. One of the 5 patients had a family history of mental retardation in male relatives, and his mother and aunt had been assessed as having intellectual impairment. All of the probands had large, soft hands with tapering fingers, severe to moderate mental retardation, short stature below the 5th centile, weight below the 5th centile, microcephaly, telecanthus or hypertelorism, and prominent eyes. Two were Caucasian; in these probands large mouth and prominent lower lips were observed. For the 3 African American probands this was difficult to evaluate because of the ethnic background.
Harum et al. (2001) noted that, based on evidence from experimental models, the transcription factor cAMP response element-binding protein (CREB; 123810) is thought to be involved in memory formation. RSK2 activates CREB through phosphorylation at serine-133. In 7 patients with CLS (5 boys and 2 girls), Harum et al. (2001) found a diminished activity of RSK2 to phosphorylate a CREB-like peptide in vitro in all cells lines. The authors noted a linear correlation between RSK2 activation of CREB and cognitive levels of the patients, consistent with the hypothesis that CREB is involved in human learning and memory. Other characteristics of the syndrome, including facial and bony abnormalities, may be due to impaired expression of various CREB-responsive genes.
By screening 250 patients with clinical features suggestive of Coffin-Lowry syndrome, Delaunoy et al. (2001) identified 71 distinct disease-associated RSK2 mutations in 86 unrelated families; 38% of the mutations were missense mutations, 20% were nonsense mutations, 18% were splicing errors, and 21% were short deletions or insertions. About 57% of the mutations resulted in premature translation termination, and most predicted loss of function of the mutant allele. The changes were distributed throughout the RSK2 gene and showed no obvious clustering or phenotypic association. However, some missense mutations were associated with milder phenotypes; in 1 family, 1 such mutation was associated solely with mild mental retardation. Nine mutations were found in female probands, with no affected male relatives, who had learning disability and mild facial and digital dysmorphism.
Zeniou et al. (2002) pointed out that in a series of 250 patients screened by SSCP analysis in whom the clinical diagnosis of CLS was made (Delaunoy et al., 2001), no mutations were detected in 165 (66%). To determine what proportion of these latter patients had an RSK2 mutation that had not been detected and what proportion have different disorders that are phenotypically similar to CLS, Zeniou et al. (2002) investigated, by Western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed them to identify 7 novel RSK2 mutations: 2 changes in the coding sequence of RSK2, 1 intragenic deletion, and 4 unusual intronic nucleotide substitutions that did not affect the consensus GT or AG splice sites. No disease-causing nucleotide change was identified in the promoter region of the RSK2 gene. The results suggested that some patients have a disorder that is phenotypically very similar to CLS but is not caused by RSK2 defects.
Delaunoy et al. (2006) analyzed the RPS6KA3 gene in 120 patients with CLS and identified 45 mutations, of which 44 were novel, confirming the high rate of new mutations at the RSK2 locus. The authors noted that no mutation was found in over 60% of the patients referred to them for screening. Delaunoy et al. (2006) stated that of the 128 CLS mutations reported to date, 33% are missense mutations, 15% nonsense mutations, 20% splicing errors, and 29% short deletion or insertion events; and 4 large deletions have been reported. The mutations are distributed throughout the RPS6KA3 gene, and most mutations are private.
In a patient with a clinical phenotype highly suggestive of CLS in whom no mutation had been identified by sequencing PCR-amplified exons of RPS6KA3 from genomic DNA, Marques Pereira et al. (2007) analyzed the gene by direct sequencing of overlapping RT-PCR products and identified a direct tandem duplication spanning exactly exons 17 to 20 (300075.0019). The authors stated that this was the first reported large duplication in the RPS6KA3 gene.
X-Linked Intellectual Developmental Disorder 19
In affected members of a family with nonsyndromic X-linked intellectual developmental disorder-19 (XLID19; 300844), Merienne et al. (1999) identified a missense mutation (300075.0010) in the RPS6KA3 gene. Patients exhibited none of the facial, digital, or skeletal features or the abnormal posture or gait typical of Coffin-Lowry syndrome.
Field et al. (2006) identified 3 different mutations in the RPS6KA3 gene (see, e.g., 300075.0020-300075.0021) in affected members of 3 unrelated families with nonsyndromic X-linked mental retardation. The patients had some variable features reminiscent of Coffin-Lowry syndrome, such as coarse facial features, kyphoscoliosis, short stature, and some redundancy of palmar skin with horizontal creases, but these additional features were considered to be too mild or atypical for a diagnosis of CLS.
The level of residual RPS6KA3 activity seems to be related to the severity of the phenotype. Merienne et al. (1999) demonstrated 10 to 20% residual enzymatic activity in patients with nonsyndromic MRX19, which was postulated to result in the relatively mild phenotype without skeletal anomalies (300075.0010). The patients reported by Field et al. (2006) with nonsyndromic X-linked mental retardation also had a milder phenotype, which the authors thought likely resulted from residual protein activity. Field et al. (2006) noted that the mutations in their report and the mutation (300075.0011) reported by Manouvrier-Hanu et al. (1999) in a family with mild Coffin-Lowry syndrome were small in-frame deletions or missense mutations affecting the serine/threonine kinase domain. Field et al. (2006) hypothesized that the presence of a small amount of residual enzymatic activity may be sufficient to maintain normal osteoblast differentiation and ameliorate the skeletal phenotype associated with CLS. The level of residual enzymatic activity has also been linked to cognitive performance, with higher levels being associated with a higher level of intellectual function (Harum et al., 2001).
Using Rsk2 -/- mice, Yang et al. (2004) showed that RSK2 is required for osteoblast differentiation and function. They identified the transcription factor ATF4 (604064) as a critical substrate of RSK2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression. Additionally, RSK2 and ATF4 were found to posttranscriptionally regulate the synthesis of type I collagen (see 120150), the main constituent of the bone matrix. Accordingly, Atf4 deficiency in mice resulted in delayed bone formation during embryonic development and low bone mass throughout postnatal life. Yang et al. (2004) concluded that ATF4 is a critical regulator of osteoblast differentiation and function and that lack of ATF4 phosphorylation by RSK2 may contribute to the skeletal phenotype of Coffin-Lowry syndrome.
David et al. (2005) demonstrated that Rsk2-null mice develop progressive osteopenia due to impaired osteoblast function and normal osteoclast differentiation. They also observed that c-fos (164810)-dependent osteosarcoma formation was impaired in the absence of Rsk2; the lack of c-fos phosphorylation led to reduced c-fos protein levels, which were thought to be responsible for the observed decreased proliferation and increased apoptosis of transformed osteoblasts. David et al. (2005) concluded that Rsk2-dependent stabilization of c-fos is essential for osteosarcoma formation in mice.
Poirier et al. (2007) found that Rsk2-null mice showed a mild impairment in spatial working memory, delayed acquisition of a spatial reference memory task, and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. The studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-null mice. There were no obvious brain abnormalities at the anatomic and histologic level. The behavioral changes observed supported a role for Rsk2 in cognitive functions.
Marques Pereira et al. (2008) found that Rsk2-null mice had increased cortical dopamine levels and overexpression of the DRD2 receptor (126450) and dopamine transporter (SLC6A3; 126455). Evidence also suggested that the dopaminergic dysregulation may have been caused, at least in part, by increased tyrosine hydroxylase (TH; 191290) hyperactivity. The authors suggested that these neurotransmitters changes may explain some of the cognitive alterations in Rsk2-null mice.
Using microarray analysis, Mehmood et al. (2011) identified 100 genes that were differentially expressed in Rsk2 -/- mice compared with wildtype, and they confirmed differential expression of 24 of these genes using quantitative RT-PCR. Genes that were affected by Rsk2 deletion had roles in cell differentiation, proliferation, apoptosis, cell cycle, free radical scavenging, and nervous system development and function. Mehmood et al. (2011) characterized the consequences of 2-fold upregulation of the Gria2 gene (138247), which encodes a subunit of the AMPA glutamate receptor. Immunohistochemical analysis revealed significantly increased surface expression of Gria2 protein in Rsk2 -/- neurons. However, patch-clamp analysis showed significantly decreased basal AMPA receptor-mediated transmission in Rsk2 -/- hippocampal neurons. These changes in Gria2 protein expression and function appeared to be due to altered Gria2 mRNA editing and splicing in Rsk2 -/- mice.
Of 76 families segregating for CLS (303600), Trivier et al. (1996) identified one in which affected members had an approximately 2-kb deletion of the RPS6KA3 gene. By RT-PCR followed by direct sequencing, they demonstrated a deletion of 187 bp between nucleotides 406 and 593. The deletion produced a frameshift, generating a TAA termination codon 33 bp downstream of the deletion junction.
In a patient with CLS (303600), Trivier et al. (1996) demonstrated a G-to-T transition at nucleotide 224 in the RSK2 gene, resulting in a gly75-to-val substitution. Gly75 is a conserved residue located within the putative ATP-binding site.
In a patient with CLS (303600), Trivier et al. (1996) demonstrated a T-to-G transition at nucleotide 679 in the RSK2 gene, resulting in a ser227-to-ala substitution. Ser227 is a conserved residue, and is believed to be a phosphorylation site of the kinase domain of the N terminus, which is essential for catalytic function.
In a familial case of CLS (303600), Jacquot et al. (1998) found a 244G-T transversion in exon 4, resulting in a val82-to-phe amino acid substitution.
Jacquot et al. (1998) identified a Coffin-Lowry syndrome (303600) pedigree in which the disorder was associated with a novel splice site mutation in the RSK2 gene, leading to in-frame skipping of exon 5: a G-to-C transition in the splice acceptor site (position -1) immediately upstream of exon 5. Western blot analysis, using an antibody directed against the C terminus of the RSK2 protein, failed to reveal RSK2 protein in this patient, suggesting strongly that the internally deleted protein was unstable. The mutation was present in the DNA of 1 affected son and 1 manifesting daughter but was absent in 2 asymptomatic daughters, who carried the at-risk haplotype, and in the mother's somatic cell (lymphocyte) DNA. The results were considered consistent with the mutation having arisen as a postzygotic event in the mother, who therefore was a germinal mosaic. The mother was clinically normal but, in addition to strong wildtype bands shown on SSCP analysis, there were very faint bands corresponding to a small proportion (less than 1%) of mutated DNA.
In 2 unrelated African American patients with CLS (303600), Abidi et al. (1999) observed an arg114-to-trp missense mutation resulting from a 340C-T nucleotide change in the RSK2 gene.
In a patient with CLS (303600), Abidi et al. (1999) found that the RSK2 gene contained a 2-bp deletion of bases 451A and 452G, causing a frameshift that resulted in a stop codon 25 amino acids downstream and thereby producing a truncated protein.
In an African American patient with CLS (303600), Abidi et al. (1999) found a 2065C-T transition that gave rise to a premature stop codon (gln689 to ter), and a truncated protein lacking the last 51 amino acids of the RSK2 gene.
In a patient with CLS (303600), Abidi et al. (1999) found a 2186G-A nucleotide change in the RSK2 gene, resulting in an arg729-to-gln missense mutation.
In affected members of a family with nonsyndromic X-linked intellectual developmental disorder-19 (XLID19; 300844), Merienne et al. (1999) identified a 1147C-T transition in exon 14 of the RPS6KA3 gene, resulting in an arg383-to-trp (R383W) substitution. This mutation occurred in a CpG dinucleotide motif. Reexamination of 2 of the affected individuals, then 38 and 29 years old, showed that they exhibited none of the facial, digital, or skeletal features or the abnormal posture or gait typical of Coffin-Lowry syndrome (303600). Furthermore, both presented with very mild mental retardation, compatible with social autonomy. It had previously been found that most CLS-producing mutations inactivate RPS6KA3. The mutation in the family reported by Merienne et al. (1999) was notable in that the 5- to 6-fold decrease in kinase activity resulted in a mild phenotype. This demonstrated that 15 to 20% of RPS6KA3 activity is sufficient for normal signaling of the MAPK-RPS6KA3 pathway involved in skeletal development.
Manouvrier-Hanu et al. (1999) reported 2 male sibs with a mild form of CLS (303600) who had a T-to-A transversion in exon 7 of the RPS6KA3 gene leading to the substitution of a lysine residue in place of an isoleucine residue at position 189 (I189K).
In a patient with Coffin-Lowry syndrome (303600), Zeniou et al. (2002) identified an IVS6+3A-G intronic mutation of the RPS6KA3 gene.
In a patient with Coffin-Lowry syndrome (303600), Zeniou et al. (2002) identified an IVS5-11A-G intronic mutation of the RPS6KA3 gene.
In a male infant native to the Cook Islands with Coffin-Lowry syndrome (303600), McGaughran and Delaunoy (2002) identified a 1-bp deletion (2144delC) in the RPS6KA3 gene, resulting in a stop codon 21 amino acids before the normal termination codon. The proband was the sixth child of nonconsanguineous parents; the fifth child, also male, died at age 7 months, presumably of the same condition. The proband's inner canthal distance was greater than the 97th centile. He had large anterior and posterior fontanels, mild synophrys, and a long philtrum. His fingers were flattened and tapering. His mother's fingers had a similar but more marked appearance. Her facial appearance was consistent with the diagnosis of heterozygous carrier of CLS, but she did not undergo molecular testing.
Fryssira et al. (2002) described a female patient with full-blown CLS (303600), manifested by facial dysmorphism, tapering fingers, and skeletal deformities (pectus excavatum and kyphoscoliosis), who was found to have an A-to-G transition in the RSK2 gene, creating a suppression of the splicing site between intron 12 and exon 13. Her overall IQ was 53. At the age of 9 years, there was onset of a cataplexy-like phenomenon characterized by a sudden and reversible loss of muscle tone without loss of consciousness.
In a patient with Coffin-Lowry syndrome (303600), Martinez-Garay et al. (2003) identified a de novo insertion of a 5-prime truncated LINE-1 element at position -8 of intron 3 of the RPS6KA3, which led to skipping of exon 4, a shift of the reading frame, and a premature stop codon. The 2,800-bp L1 fragment showed a rearrangement with a small deletion and a partial inversion of ORF2, flanked by short direct repeats that duplicated the acceptor splice site. A cDNA analysis showed that both sites were apparently nonfunctional. The 30-year-old patient had mental retardation, hypotonia, sensorineural hearing deficit, downslanting palpebral fissures, broad nose, anteverted nares, large mouth, thick everted lips, large and everted ears, pectus carinatum, tapering fingers with drumstick terminal phalanges, forearm fullness, and flat feet.
In monozygotic twins with Coffin-Lowry syndrome (303600) and in their mother, who was mildly affected, Martinez-Garay et al. (2003) identified an 803T-C transition in exon 10 of the RPS6KA3 gene, which resulted in a phe268-to-ser (F268S) substitution. The mother showed tapering fingers, obesity, large mouth, and large and dysplastic ears.
In a 14-year-old boy with physical and developmental findings consistent with Coffin-Lowry syndrome (303600), Facher et al. (2004) identified a 3-bp deletion (TAT) at position 1428 of the RPS6KA3 gene, resulting in the loss of an isoleucine. The patient was unusual in that he had restrictive cardiomyopathy.
In an 1.5-year-old boy with Coffin-Lowry syndrome (303600), Marques Pereira et al. (2007) identified an in-frame tandem duplication of exons 17 to 20, resulting from insertion of 516 nucleotides at nucleotide 1959, that arose from a homologous unequal recombination between Alu sequences. In vitro kinase assay showed that mutant RSK2 was inactive. The patient's mother, who had childhood scoliosis and difficulties in school, was found to carry the mutation.
In affected members of a family with nonsyndromic X-linked intellectual developmental disorder-19 (XLID19; 300844), Field et al. (2006) identified an in-frame 3-bp deletion (454delGGA) in the RPS6KA3 gene, resulting in the deletion of gly152. This residue is highly conserved and located in the serine/threonine protein kinase domain. The patients had coarse facial features, kyphoscoliosis, and some redundancy of palmar skin with horizontal creases, but no digital tapering or short stature. These additional features were considered to be too mild for a diagnosis of Coffin-Lowry syndrome (303600). Field et al. (2006) hypothesized that the mutant protein had a small amount of residual activity, which likely explained the relatively mild phenotype.
In 3 brothers with nonsyndromic X-linked intellectual developmental disorder-19 (XLID19; 300844), Field et al. (2006) identified a 343A-T transversion in the RPS6KA3 gene, resulting in a thr115-to-ser (T115S) substitution in a highly conserved region in the serine/threonine protein kinase domain. The patients had short stature, hypertelorism, and a slightly full lower lip, but these features were considered to be too subtle for a diagnosis of Coffin-Lowry syndrome (303600). Field et al. (2006) hypothesized that the mutant protein had a small amount of residual activity, which likely explained the relatively mild phenotype.
In cells derived from an affected member of the original family with Coffin-Lowry syndrome (CLS; 303600) reported by Lowry et al. (1971), Nishimoto et al. (2014) identified an in-frame deletion of exons 15 and 16 (r.1228_1443del216) in the RPS6KA3 gene, resulting in the deletion of 72 amino acids from 410 to 418 in the C-terminal kinase domain, predicting the loss of function of this domain. Microarray analysis indicated that the maximum size of the deletion was about 7.2 kb.
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