RPS6KA3

  • 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
RPS6KA3 (HGNC:10432) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
ribosomal protein S6 kinase A3
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
MRX19, CLS
Alias symbols
RSK2, HU-3
%HI
4.88(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.09(Read more about gnomAD LOEUF score)
Cytoband
Xp22.12
Genomic Coordinates
GRCh37/hg19: chrX:20168029-20285027 NCBI Ensembl UCSC
GRCh38/hg38: chrX:20149911-20267097 NCBI Ensembl UCSC
MANE Select Transcript
NM_004586.3 ENST00000379565.9 (Read more about MANE Select)
Function
Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro- apoptotic function of BAD and DAPK1 (PubMed:9770464, PubMed:16223362, PubMed:17360704, PubMed:16213824). In ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-36806
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
06/14/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 8955270
    Trivier et al. (1996) analyzed RPS6KA3 (known as RSK2 in this manuscript) for variants in 76 unrelated patients with Coffin-Lowry Syndrome (CLS). They found 6 variants: 1 intragenic deletion, 1 nonsense, 2 splice site, and 2 missense. The intragenic deletion was ~2 kb and resulted in a frameshift and stop codon.
  • PUBMED: 9837815
    Jacquot et al. (1998) analyzed RPS6KA3 (known as RSK2 in this manuscript) for variants in 37 patients with CLS. They found 25 variants: 7 nonsense, 5 frameshift, 8 splice site, and 5 missense.
  • PUBMED: 16879200
    Delaunoy et al (2006) reported on 42 novel variants and 1 previously reported variants detected in 120 patients worldwide referred to them with suspected CLS. They detected 4 nonsense, 6 splice site alterations, 19 short deletions and/or insertions (or duplication) (two in-frame deletions of one codon (c.605_607delATG and c.1428_1430delTAT) and the others causing a frameshift resulting in premature truncation), 1 large deletion and 13 amino acid substitutions (for one mutation, p.Arg729Trp, no RSK2 protein was detectable by western blot analysis). In 44 of a total of 66 (67%) families, in which proband’s mother could be analyzed, the variant was not detected in the mother. Evidence for germinal mosaicism was demonstrated in two families. The authors summarize their cases plus 84 previously reported variants which supports a loss of function mechanism: "The spectrum of mutations includes 37 short insertion or deletion events in the coding sequence (29%), 4 large genomic deletions encompassing one to three exons (3%), 25 splice site alterations (20%), 19 nonsense (15%), and 42 missense mutations (33%). In addition, a de novo insertion of a 5′-truncated LINE-1 element at position −8 of intron 3, leading to skipping of exon 4, was reported in one family 11. In total, at least 66% of these mutations can be predicted to cause directly or indirectly a premature termination codon. Of the 128 RSK2 mutations so far identified, 114 were private mutations found in only one family. Of 14 mutations found in more than one family, 5 were in three families and 9 in two families. Seven of these recurrent mutations occurred at CpG dinucleotides."
  • PUBMED: 26297997
    Labonne et al (2018) reported a male patient with CLS having a novel variant at the 3' end of an exon at a splice donor junction. The nucleotide change causes both a novel missense variant and partial exon skipping leading to a truncated transcript. In the carrier mother (who had a mild phenotype) they found only wildtype transcripts, suggesting skewed X-inactivation, which was confirmed by methylation studies.
  • PUBMED: 31400053
    Fung et al (2019) reported nine Chinese CLS patients from six unrelated families (three with familial variants and three with de novo variants). Their report included frameshift, exonic deletion, nonsense, splice site and missense mutations with patients with CLS. They noted that the clinical phenotype and facial features of these Chinese CLS patients are comparable to what has been described in other groups.
HI Evidence Comments:
Loss of function of RPS6KA3 cause Coffin-Lowry Syndrome (CLS), which is a recognizable phenotype associated with severe to profound intellectual disability in males. Facial dysmorphism, digit abnormalities, progressive skeletal deformations, growth retardation, hearing deficit, paroxysmal movement disorders are also reported. Phenotypes ranging from normal to severe have been reported in carrier females.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
Madrigal et al. (2007) (PMID: 17304053) used MLPA and arrayCGH to identify a 1 Mb duplication including the CXorf23, FLJ14503, EIF1AX, and RPS6KA3 genes. The duplication was found in the male proband, 2 affected family members (male cousin and uncle), and the 2 female carriers. The proband did not display feature of CLS, but had nonspecific ID and a "robust build". Tejada et al. (2011) PMID: 21930553 used MLPA and arrayCGH to identify a 1 Mb duplication involving 7 genes (SH3KBP1, BC046187, CXorf23, MAP7D2, EIF1AX, SCARNA9L, and RPS6KA3) in a proband with mild ID. His brother, 2 uncles, mother, and grandmother also carried the duplication. The uncles had learning difficulties and delayed language in childhood; the brother also had LD, but not as severe as the proband. The mother and grandmother did not have LD.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)