New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia

Abstract

Despite recent progress in our understanding of renal magnesium (Mg 2 þ ) handling, the molecular mechanisms accounting for transepithelial Mg 2 þ transport are still poorly understood. Mutations in the TRPM6 gene, encoding the epithelial Mg 2 þ channel TRPM6 (transient receptor potential melastatin 6), have been proven to be the molecular cause of hypomagnesemia with secondary hypocalcemia (HSH; OMIM 602014). HSH manifests in the newborn period being characterized by very low serum Mg 2 þ levels (o0.4 mmol/l) accompanied by low serum calcium (Ca 2 þ ) concentrations. A proportion of previously described TRPM6 mutations lead to a truncated TRPM6 protein resulting in a complete loss-of-function of the ion channel. In addition, five-point mutations have been previously described. The aim of this study was to complement the current clinical picture by adding the molecular data from five new missense mutations found in five patients with HSH. To this end, patch-clamp analysis and cell surface measurements were performed to assess the effect of the various mutations on TRPM6 channel function. All mutant channels, expressed in HEK293 cells, showed loss-of-function, whereas no severe trafficking impairment to the plasma membrane surface was observed. We conclude that the new TRPM6 missense mutations lead to dysregulated intestinal/renal Mg 2 þ (re)absorption as a consequence of loss of TRPM6 channel function.

Regulation of Mg2+ Reabsorption and Transient Receptor Potential Melastatin Type 6 Activity by cAMP Signaling

“…4,5 Loss-of-function mutations in TRPM6 are the primary cause of inherited hypomagnesemia with secondary hypocalcemia. [6][7][8] Inactivation of TRPM6 in mice is lethal, whereas heterozygous deletion of Trpm6 or chemical damage to the DCT is associated with hypomagnesemia. [9][10][11] In addition to TRPM6, various transporters and channels are proposed to either directly mediate Mg 2+ reabsorption or indirectly stimulate it by maintaining a favorable electrochemical gradient.…”

Expressions of TRPM6 and TRPM7 and histopathological evaluation of tissues in ischemia reperfusion performed rats

“…A missense mutation in the coding region of the TRPM6 gene is characterized by the reduced expression of this protein and subsequently decreased the magnesium uptake. 14 The role of magnesium in renal system is not fully understood but hyper-or hypo-magnesium levels are known to create significant kidney problems. According to our literature searches, the role of TRPM6 in renal ischemia-reperfusion has not been elucidated yet.…”

Genetics of Magnesium Disorders

“…HSH patients typically present during the first few months of life with neurological symptoms of tetany and seizures associated with profound hypomagnesemia and secondary hypocalcemia due to parathyroid failure. HSH is associated with the most severe hypomagnesemia among all genetic forms of channelopathy, in the range of 0.05-0.20 m M in a recent study [48] , due to the dual defects in gastrointestinal and renal Mg 2+ absorption. To date, fewer than 50 unique mutations in TRPM6 have been recorded [48] .…”

“…HSH is associated with the most severe hypomagnesemia among all genetic forms of channelopathy, in the range of 0.05-0.20 m M in a recent study [48] , due to the dual defects in gastrointestinal and renal Mg 2+ absorption. To date, fewer than 50 unique mutations in TRPM6 have been recorded [48] . Most of the mutations are predicted to give rise to a premature termination of TRPM6 in approximately 85% of the mutations tested.…”

“…In the C terminus, there is an α-kinase domain that plays a regulatory role in response to RACK-1 and REA. These regions are all targets of potential signaling interactions [47,48] . Thus, it comes as no surprise that TRPM6 can be activated by a number of signals including EGF, insulin, estrogen, purinergic signaling, dietary Mg 2+ intake, and acid-base alterations.…”