Genetic disorders

Coffin-Lowry syndrome; Alpha-thalassemia/mental retardation syndrome; Partington syndrome; Estrogen resistance; Mental retardation, X-linked 17/31, Microduplication

Coffin-Lowry Syndrome (CLS) is a rare genetic disorder characterized by craniofacial (head and face) and skeletal abnormalities, mental retardation, short statue, and hypotonia. Characteristic symptoms include hypertonia/spasticity, lens ossification, retinal pigment changes, feeding and respiratory problems, developmental delay, mental retardation, and heart and kidney defects. Several mutations in the RPS6KA3 gene have been observed in patients with CLS. In 86 unrelated families with CLS, 71 distinct disease-associated mutations were identified in the RPS6KA3 gene. The observed mutations included missense mutations (38%), nonsense mutations (20%), splicing errors (18%), and short deletions or insertions (21%). The mutations were distributed throughout the gene and did not display clustering of phenotypic association, indicating a loss-of-function effect on the RPS6KA3 protein. In animal studies, knockout of RPS6KA3 in mice lead to failure of osteoblast differentiation, resulting in abnoramlly delayed bone formation during development resulting in significantly reduced bone mass in the adult mice. Therefore, loss-of-function in the RPS6KA3 protein may play a role in the pathogenesis of Coffin-Lowry syndrome.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +57, p<0.013); and Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +382, p<0.0008). The COSMIC website notes an up-regulated expression score for RSK2 in diverse human cancers of 466, which is very close to the average score of 462 for the human protein kinases. The down-regulated expression score of 125 for this protein kinase in human cancers was 2.1-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.09 % in 25463 diverse cancer specimens. This rate is only 23 % higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.46 % in 1119 large intestine cancers tested; 0.43 % in 1278 liver cancers tested; 0.36 % in 602 endometrium cancers tested; 0.09 % in 1503 breast cancers tested; 0.08 % in 1941 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: Y483C (4); L381P (3).

Ten deletions, 4 insertions and 5 complex mutations are noted on the COSMIC website.