Endocrine disorders

Insulin resistance; Immunodeficiency 15

Insulin resistance is a disease characterized by a failure of cells to respond to normal levels of circulating insulin, resulting in hyperglycemia due to impaired glucose uptake. This causes an overproduction of insulin by the beta cells in the pancreas, which leads to hyperinsulinemia, and can contribute to the development of Type 2 diabetes or latent autoimmune diabetes in adults. immunodeficiency-15 (IMD15) is a immune disease characterized by the development in infants of severe bacterial, fungal, and viral infections, resulting in a failure to thrive. This disease is inherited in an autosomal recessive manner and results from defects in the differentiation and subsequent activation of immune cells (e.g. T and B cells). Mutations in the IKKb gene have been observed in patients with the IMD15 phenotype, including a 1-bp duplication mutation (c.1292dupG) in exon 13 of the gene resulting in a frameshift and premature truncation of the protein and loss of the alpha-helical dimerization domain, as well as a transition mutation resulting in an R272X mutation producing a truncated, non-functional protein correlated with the absence of memory B-cells and very low numbers of memory T-cells. In animal studies, mice lacking a functional IKKb protein specifically in myeloid cells displayed higher mortality when exposed to endotoxin, indicating a compromised immune system. In addition, the prolonged pharmacological inhibition of IKKb resulted in an increase in lipopolysaccharide-induced mortality in mice. Furthermore, inflammation has been proposed as a central component of several metabolic disorders, such as insulin resistance and type 2 diabetes. IKKb is a key coordinator of inflammatory responses through its role in the activation of NF-KB, indicating a potential mechanistic link. Interestingly, mice that lack IKKb expression in myeloid cells display the maintenance of insulin sensitivity and failure to develop insulin resistance even in response to a high fat diet, aging, or obesity.
 

IKKb may be a tumour requiring protein (TRP), since it displays extremely low rates of mutation in human cancers.
 

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= +105, p<0.009); Brain glioblastomas (%CFC= -84, p<0.049); Brain oligodendrogliomas (%CFC= -87, p<0.044); Breast epithelial hyperplastic enlarged lobular units (HELU) (%CFC= +90, p<0.088); Cervical cancer stage 1B (%CFC= +83, p<0.061); and Cervical cancer stage 2B (%CFC= +115, p<0.051). The COSMIC website notes an up-regulated expression score for IKKb in diverse human cancers of 666, which is 1.4-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 171 for this protein kinase in human cancers was 2.9-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: 0.01 % in 25958 diverse cancer specimens. This rate is -90 % lower than the average rate of 0.075 % calculated for human protein kinases in general. Such a very low frequency of mutation in human cancers is consistent with this protein kinase playing a role as a tumour requiring protein (TRP).

Highest percent mutation rates per 100 amino acids length in human cancers: 0.05 % in 2314 haematopoietic and lymphoid cancers tested; 0.01 % in 1683 breast cancers tested.

Most frequent mutations with the number of reports indicated in brackets: K171E (8); K171T )2).

Only 5 deletions, no insertions or complex mutations are noted on the COSMIC website.