Developmental disorders

Cardiofaciocutaneous syndrome; Cardiofaciocutaneous syndrome 3; Leopard syndrome; MAP2K1-related Noonan syndrome; MAP2K1-related cardiofaciocutaneous (CFC) syndrome

Cardio-facio-cutaneous (CFC) syndrome is a disease characterized by abnormalities found in numerous parts of the body, particularly the heart, face, skin, and hair. Affected individuals display developmental delay and intellectual disability, ranging from moderate to severe. This disease is inherited in an autosomal dominant manner. Leopard syndrome is a genetic disease characterized by abnormalities in the heart, skin, inner ears, and genitalia. Most cases of this disease are inherited in an autosomal dominant manner. Noonan syndrome is a genetic disease characterized by the abnormal development of many parts of the body. Affected individuals display abnormal facial features, short stature, heart defects, and often delayed development. Mutations in the MEK1 gene have been observed in patients with CFC syndrome, including the F53S, Y130C, and G128V substitution mutations. MEK1 proteins containing the F53S and Y130C substitution mutations were shown to be unable to activate ERK/MAPK signalling unless they were phosphorylated by Raf at two serine phosphosites in the regulatory loop of the protein. Mutations in the MEK1 gene were observed in 5 out of 51 (9.8%) CFC syndrome patients, indicating a role for abnoraml MEK1 activity in the pathogenesis of the disease. In addition, ~60% of reported cases of Noonan syndrome are caused by mutations in proteins of the Ras-MAPK signalling pathway, specifically mutations that result in a gain-of-function of Raf protein activity. As MEK1 is an upstream activator of the Ras-MAPK signalling pathway, it has been implicated in the development of Noonan syndrome. Additionally, transgenic mice with overexpressed MEK1 protein specifically in the cardiomyocytes displayed substantial cardiac hypertrophy with the preservation of contractile function, indicating a link between MEK1 and cardiac disease, a common symptom of Noonan 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: Barrett's esophagus epithelial metaplasia (%CFC= -52, p<0.003); Bladder carcinomas (%CFC= +92, p<0.0002); Breast epithelial carcinomas (%CFC= -48, p<0.07); Cervical epithelial cancer (%CFC= +45, p<0.016); Prostate cancer - primary (%CFC= -76, p<0.0001); and Uterine fibroids (%CFC= +62, p<0.014). The COSMIC website notes an up-regulated expression score for MEK1 in diverse human cancers of 398, which is 0.9-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 107 for this protein kinase in human cancers was 1.8-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.18 % in 31616 diverse cancer specimens. This rate is 2.3-fold 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: 1.22 % in 1379 skin cancers tested; 0.66 % in 1384 large intestine cancers tested; 0.45 % in 681 stomach cancers tested; 0.39 % in 2046 haematopoietic and lymphoid cancers tested; 0.14 % in 5486 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: P124S (29); K57N (16); C121S (10); E203K (9); D67N (9); F53L (8); P124L (5).

Twelve deletions, no insertions and 2 complex mutations are noted on the COSMIC website.