Cancer, gastrointestinal disorders

Meconium ileus; Diarrhea; Ileus; Chronic diarrhea due to guanylate cyclase 2c overactivity; Intestinal obstruction

Meconium ileus, also known as intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency, is related to cystic fibrosis and diarrhea. The affected tissues in this disease include the pancreas, liver, and small intestine. This disease is characterized by the blockage of the baby's bowel at birth by the contents of the bowel (meconium). Roughly 90% of affected babies also have cystic fibrosis, as the blockage is a result of cystic fibrosis due to the production of a large quantity of an extremely sticky substance in the bowel. Meconium ileus is a rare disease, affecting only 1 in 25,000 births. Diarrhea is characterized by loose stools, which can be caused by bacteria, viruses, parasites, certain medicines, intolerances of certain foods, and gastrointestinal diseases. Mutations in the HSER gene have been linked to meconium ileus. In particular, a D387G substitution mutation was identified from a large Bedouin family with high rates of meconium ileus occurence. This mutation occurs at a conserved residue within one of the essential regions of the extracellular ligand-binding domain of the protein, thus it is associated with a loss-of-function. In vitro studies performed in HEK293 cells revealed that the mutant D387G protein had 60% lower activity than the wild type protein, confirming the loss-of-function phenotype. Additionally, in a sporadic case of meconium ileus a 1-bp duplication mutation was observed (2270dupA). This mutation caused a frameshift that resulted in the truncation of the catalytic domain of the protein (Asn757Lysfs*2), producing a non-functional HSER protein. In addition to meconium ileus, mutations in the HSER gene have been linked to the occurence of diarrhea. In particular, studies of a large pedigree of autosomal early-onset chronic diarrhea revealed a S840I substitution mutation in exon 22 of the HSER gene. This mutation occurs at a highly conserved residue in the catalytic domain of the protein. In vitro analysis of the S840I mutant HSER protein revealed a significantly elevated level of cGMP production as compared to the wild-type protein, indicating that the mutation produced a gain-of-function in the activity of the HSER protein that contributed to the pathogenesis of early-onset diarrhea. HSER binds to bacterially-derived heat-stable enterotoxin causing an elevation of cGMP in the cell and enhanced water and chloride secretion. Exposure to the heat-stable enterotoxin leads to secretory diarrhea due to the increased water secretion in the intestines. As a guanylate cyclase, when stimulated by the heat-stable enterotoxin, HSER catalyzed the conversion of GTP to cGMP elevating cellular cGMP levels, thus a gain-of-function in the HSER protein is implicated in suceptibility to the toxin.
 

Ovarian mucinous neoplasms

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 glioblastomas (%CFC= -54, p<0.086); and Colorectal adenocarcinomas (early onset) (%CFC= -60, p<0.0001). The COSMIC website notes an up-regulated expression score for HSER in diverse human cancers of 261, which is 0.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 5 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 only 30 % 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: 0.72 % in 864 skin cancers tested; 0.29 % in 1270 large intestine cancers tested; 0.26 % in 603 endometrium cancers tested; 0.21 % in 833 ovary cancers tested; 0.17 % in 1634 lung cancers tested; 0.14 % in 589 stomach cancers tested; 0.13 % in 1512 liver cancers tested; 0.11 % in 1316 breast cancers tested; 0.08 % in 942 upper aerodigestive tract cancers tested; 0.08 % in 710 oesophagus cancers tested; 0.08 % in 238 bone cancers tested; 0.05 % in 548 urinary tract cancers tested; 0.04 % in 1276 kidney cancers tested; 0.03 % in 2082 central nervous system cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R319* (4); T946K (4).

Multiple deletions in the C-terminal half of the protein, which encompasses the kinase and guanylate cyclase domains.