Cancer, growth disorders

Brachydactyly Type A2

Brachydactyly Type A2 symptoms include clinodactyly (fifth finger), and short hand/brachydactyly. Important pathways in this syndrome are the mTOR and apopotosis pathways. Bone tissue may be affected in this condition. Loss of function of BMPR1A may induce Brachydactyly Type A2, as a reduction of growth and differentiation factor 5 (GDF5) interaction with BMPR1A also produced this disease.
 

Juvenile polyposis syndrome; Juvenile polyposis syndrome, infantile Form; Bannayan-Riley-Ruvalcaba syndrome; Ruvalcaba syndrome; Juvenile polyposis of Infancy; Hereditary mixed polyposis syndrome 2; BMPR1A-related juvenile polyposis; Cowden disease; Colorectal cancer, Hereditary nonpolyposis, Type 1

BMPR1A appears to be a tumour suppressor protein (TSP). Cancer-related mutations in human tumours point to a loss of function of the protein kinase. The active form of the protein kinase normally acts to inhibit tumour cell proliferation. Juvenile Polyposis Syndrome (JPS) can lead to polyp formation, often in the large bowel, and the disorder can lead to an increased risk of cancer. Multiple mutations in BMPR1A have been described in JPS patients. Bannayan-Riley-Ruvalcaba Syndrome is a rare disorder with mutations in PTEN, relates to Juvenile Polyposis Syndrome, and is characterized by macrocephaly, intestinal polyposis, lipomas, and pigmentation in the region of the glans penis. Tissues affected included skin, thyroid, and breast. Ruvalcaba Syndrome have mutations in pten, and are associated with an inositol metabolism pathway. Tissues affected in Ruvalcaba Syndrome include testes, skin, and kidneys. Cowden Disease is characterized by hamartoma growths (non-cancerous, tumour-like) but will also correlate with an increased risk of developing various cancers including breast, thyroid, and uterine endometrium. Cowden is from a mutation in the PTEN, SDHD, and KLLN genes and is associated with the cerebellum, breast, and thyroid. Mouse insertional mutagenesis experiments support BMPR1A as a cancer driver gene.
 

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: Brain oligodendrogliomas (%CFC= -95, p<0.064); Cervical cancer stage 2B (%CFC= -51, p<0.101); Colorectal adenocarcinomas (early onset) (%CFC= +46, p<0.08); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +48, p<0.074); Oral squamous cell carcinomas (OSCC) (%CFC= +149, p<0.0001); Prostate cancer - primary (%CFC= -54, p<0.0001); and Skin squamous cell carcinomas (%CFC= -47, p<0.004). The COSMIC website notes an up-regulated expression score for BMPR1A in diverse human cancers of 328, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 130 for this protein kinase in human cancers was 2.2-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: 0.08 % in 25763 diverse cancer specimens. This rate is the same as 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: 0.51 % in 1243 large intestine cancers tested; 0.14 % in 1941 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R486L (6); R486Q (3); R486W (2);.

Only 2 deletions, 1 insertion, and no complex mutations are noted on the COSMIC website.