Cancer, neurological disorders

Narcolepsy

Nacrolepsy, also known as hypnolepsy, is a neurological disease characterized by the inability of the brain to properly regulate sleep-wake cycles. Symptoms of this disease include excessive daytime sleepiness and cataplexy, which is a sudden onset, transient occurence of muscle weakness with full conscious awareness. Nacrolepsy is throught to result from the autoimmune degeneration of hypocretin/orexin-producing neurons in the brain, which are critical to the regulation of sleep-wake cycles. Elevated levels of antibodies directed against TRIB2 (anti-TRIB2) have been observed in patients with nacrolepsy, indicating that an anti-TRIB2 antibody-mediated degeneration of hypocretin/orexin-producing neurons may contribute to the pathogenesis of nacrolepsy. However, it is unknown as to whether the anti-TRIB2 antibodies cause damage to the hypocretin/orexin-producing neurons.
 

Acute myelogenous leukemias (AML)

Trb2 may be an oncoprotein (OP). In animal studies, mice injected with hemapoietic stem cells (HSC) that over-expressed Trb2 displayed a uniform development of acute myelogenous leukemia (AML), indicating a role for Trb2 in the pathogenesis of AML. In addition, Trb2 over-expression is associated with the degradation of C/EBPalpha, a transcription factor that is commonly mutated in patients with AML.
 

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= +188, p<0.016); Bladder carcinomas (%CFC= +68, p<0.051); Brain glioblastomas (%CFC= -60, p<0.057); Cervical cancer (%CFC= -64, p<0.0007); Cervical cancer stage 2A (%CFC= -50, p<0.076); Colorectal adenocarcinomas (early onset) (%CFC= +171, p<0.003); Oral squamous cell carcinomas (OSCC) (%CFC= +234, p<0.0001); Ovary adenocarcinomas (%CFC= +130, p<0.003); Prostate cancer (%CFC= -51, p<0.091); Skin fibrosarcomas (%CFC= +752, p<0.003); Skin melanomas - malignant (%CFC= +952, p<0.0001); Uterine leiomyomas (%CFC= -69, p<0.032); and Uterine leiomyomas from fibroids (%CFC= +71, p<0.057). The COSMIC website notes an up-regulated expression score for Trb2 in diverse human cancers of 404, which is 0.9-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 3 for this protein kinase in human cancers was 0.1-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 24726 diverse cancer specimens. This rate is a modest 1.4-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: 0.6 % in 1270 large intestine cancers tested; 0.58 % in 603 endometrium cancers tested; 0.4 % in 589 stomach cancers tested; 0.27 % in 864 skin cancers tested; 0.25 % in 1634 lung cancers tested; 0.16 % in 710 oesophagus cancers tested; 0.11 % in 548 urinary tract cancers tested; 0.11 % in 273 cervix cancers tested; 0.09 % in 1316 breast cancers tested; 0.07 % in 1276 kidney cancers tested; 0.04 % in 1459 pancreas cancers tested; 0.03 % in 881 prostate cancers tested; 0.03 % in 2082 central nervous system cancers tested; 0.01 % in 2009 haematopoietic and lymphoid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: S515S (7); R268Q (3).

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