Metabolic disorders

Hypomagnesemia with secondary hypocalcemia; Hypomagnesemia 1, intestinal

Hypomagnesia with secondary hypocalcemia (HSH) is a genetic disease characterized by decreased intestinal magnesium absorption. Reduced serum magnesium levels are thought to result in decreased production of parathryoid hormone (PH) by the parathyroid gland, which leads to reduced serum calcium levels, thus causing secondary hypocalcemia. HSH is characterized by low serum levels of Mg2+ due to defects in intestinal Mg2+ absorption and/or excessive expulsion of Mg2+ at the kidneys. Autosomal recessive HRH is caused by mutations in the TRPM6 gene. TRPM6 is an ion channel and serine/threonine kinase that is crucial for magnesium homeostasis. TRPM6 functions in the active epithelial tranport of magnesium in the intestine and kidney, thus serving a critical role in the absorption of dietary magnesium. Therefore, loss-of-function mutations in the TRPM6 gene that result in defective magnesium transport are thought to be key conrtibutors to the development of HSH. Several mutations of the TRPM6 gene have been identified in patients with HSH including a S590X nonsense mutation, a splice site mutation causing exon skipping, frameshift mutations resulting in truncation of the TRPM6 protein, a R484X nonsense mutation, a R56X nonsense mutation, and a S141L mutation. To form functional ion channels at the cellular membrane, TRPM6 proteins oligomerize with TRMP7 proteins to form a protein complex at the cell surface. The observed S141L mutation prevents the oligomerization of TRPM6 and TRPM7 proteins, thus preventing the formation of functional ion channels and inhibiting magnesium absorption, thus leading to the HSH phenotype.
 

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= -60, p<0.0008); and Colon mucosal cell adenomas (%CFC= -95, p<0.0001). The COSMIC website notes an up-regulated expression score for ChaK2 in diverse human cancers of 370, which is 0.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than 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 24727 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: 0.55 % in 864 skin cancers tested; 0.27 % in 1270 large intestine cancers tested; 0.24 % in 589 stomach cancers tested; 0.22 % in 603 endometrium cancers tested; 0.22 % in 1635 lung cancers tested; 0.13 % in 273 cervix cancers tested; 0.12 % in 1512 liver cancers tested; 0.1 % in 548 urinary tract cancers tested; 0.09 % in 710 oesophagus cancers tested; 0.08 % in 942 upper aerodigestive tract cancers tested; 0.08 % in 881 prostate cancers tested; 0.08 % in 1276 kidney cancers tested; 0.06 % in 238 bone cancers tested; 0.06 % in 1316 breast cancers tested.

Most frequent mutations with the number of reports indicated in brackets: V875F (11); E1150G (3).

Only 3 deletions, no insertions or complex mutations.