Coffin-Lowry syndrome (CLS) is an X-linked disease in humans characterized by intellectual disability, distinctive facial features, and short stature; CLS exhibits X-linked dominant inheritance. The gene implicated in this disease is RPS6KA3, which encodes a member of the ribosomal S6 kinase family of growth-factor-regulated serine/threonine protein kinases. This gene is also associated with a nonsyndromic form of mental retardation, MRX19 (MIM:300844). There is a high-scoring ortholog in flies, S6kII, for which classical hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\S6kII is orthologous to several other ribosomal S6 kinases in human, RPS6KA2, RPS6KA1, and RPS6KA6.
A UAS construct of the wild-type human Hsap\RPS6KA3 gene has been introduced into flies, but has not been characterized.
Loss-of-function mutations in Dmel\S6kII result in learning and memory defects; plus physiological defects in motor neurons, neuromuscular junctions, photoreceptors, and other neural cells. Many physical and genetic interactions have been described for Dmel\S6kII; see below and in the S6kII gene report.
A variant implicated in human disease has been introduced into flies, but has not been characterized. Variant(s) implicated in human disease (analogous mutation in fly gene): K347E in the fly S6kII gene (corresponds to K216E in the human RPS6KA3 gene).
[updated Apr. 2020 by FlyBase; FBrf0222196]
[COFFIN-LOWRY SYNDROME; CLS](https://omim.org/entry/303600)
[RIBOSOMAL PROTEIN S6 KINASE A3; RPS6KA3](https://omim.org/entry/300075)
Coffin-Lowry syndrome (CLS) is a rare form of X-linked mental retardation characterized by skeletal malformations, growth retardation, hearing deficit, paroxysmal movement disorders, and cognitive impairment (Kesler et al., 2007; pubmed:17318637). [from MIM:303600; 2016.03.28]
The gene implicated in Coffin-Lowry syndrome is ribosomal S6 kinase A3 (RPS6KA3) on the X chromosome. CLS acts as a semi-dominant, with symptoms appearing in some carrier females. [from MIM:303600; 2016.03.28]
The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase) family of growth-factor-regulated serine/threonine protein kinases. RSK proteins contain 2 functional kinase catalytic domains: an N-terminal kinase domain of the AGC kinase family and a C-terminal kinase domain of the CamK family. RSK proteins are directly phosphorylated and activated by MAPK proteins in response to growth factors, polypeptide hormones, and neurotransmitters, and then subsequently phosphorylate many substrates (review by Marques Pereira et al., 2010; pubmed:19888300). [from MIM:300075; 2016.03.28]
Many to one: 4 human to 1 Drosophila; the fly gene S6kII is orthologous to RPS6KA3 (reciprocal best hit), RPS6KA2 (reciprocal best hit), RPS6KA1, and RPS6KA6 in humans.
High-scoring ortholog of human RPS6KA3 and RPS6KA2; moderate-scoring ortholog of RPS6KA1 and RPS6KA6 (1 Drosophila to multiple human). Dmel\S6kII shares 55-57% identity and 69-71% similarity with these human genes.
