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
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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)
Haploinsufficiency (HI) Score Details
- Coffin-Lowry syndrome Monarch
-
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.
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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.
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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."
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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.
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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.
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
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.