Immune disorders

Agammaglobulinemia, X-linked 1; Bruton-Type agammaglobulinemia; Agammaglobulinemia; Wiskott-Aldrich syndrome; Growth hormone deficiency; Isolated growth hormone deficiency; Agammaglobulinemia and isolated hormone deficiency; Poliomyelitis; B-cell deficiency; Paralytic poliomyelitis; Fabry disease; Isolated growth hormone deficiency Type 3

Agammaglobulinemia is a humoral immunodeficiency disease characterized by the defective development and maturation of B-cells. Affected individuals have very low (if not complete absent) levels of circulating B-cells, resulting in the complete absence of all classes of immunoglobulins in their body. As a result, patients with this disease suffer from chronic bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis, and even sepsis and meningitits. Treatment for this disease is usually through the intravenous infusion of immunoglobins. Numerous loss-of-function mutations in the BTK gene have been observed in agammaglobulinemia patients, and are thought to be the cause of the failed B-cell maturation in this disease. About 80-90% of males with X-linked ammaglobulinemia have mutations in the BTK gene. In total, 544 unique mutations spread across all 5 domains of the BTK protein have been reported with an association to agammaglobulinemia, with the most common being missense mutations. Most of the observed mutations result in premature translational termination leading to truncation of the BTK protein product. Interestingly, around one-third of the observed point mutations were located in CpG sites forming arginine residues. In animal studies, introduction of BTK protein from the pre-B cell stage onwards in BTK-deficient mice effectively rescued the immunodeficient phenotype, restoring the maturation of B-cells, normal serum immunoglobulin levels, and a normal in vivo immune response to introduced pathogens.
 

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= -48, p<0.002); Brain glioblastomas (%CFC= -87, p<0.031); Cervical cancer stage 1B (%CFC= +258, p<0.003); Cervical cancer stage 2A (%CFC= +110, p<0.066); Cervical cancer stage 2B (%CFC= +313, p<0.066); and Colon mucosal cell adenomas (%CFC= -70, p<0.0001); The COSMIC website notes an up-regulated expression score for BTK in diverse human cancers of 494, which is 1.1-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 113 for this protein kinase in human cancers was 1.9-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: 0.1 % in 25448 diverse cancer specimens. This rate is only 29 % 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: 0.47 % in 805 skin cancers tested; 0.35 % in 1093 large intestine cancers tested; 0.33 % in 602 endometrium cancers tested; 0.24 % in 1941 lung cancers tested; 0.1 % in 1466 breast cancers tested.

None > 4 in 20,629 cancer specimens

Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.