Article ; Online: New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia.
European journal of human genetics : EJHG
2013 Volume 22, Issue 4, Page(s) 497–504
Abstract: ... surface was observed. We conclude that the new TRPM6 missense mutations lead to dysregulated intestinal ... have been proven to be the molecular cause of hypomagnesemia with secondary hypocalcemia (HSH; OMIM ... to complement the current clinical picture by adding the molecular data from five new missense mutations found ...
| Abstract | Despite recent progress in our understanding of renal magnesium (Mg(2+)) handling, the molecular mechanisms accounting for transepithelial Mg(2+) transport are still poorly understood. Mutations in the TRPM6 gene, encoding the epithelial Mg(2+) 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+) levels (<0.4 mmol/l) accompanied by low serum calcium (Ca(2+)) 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+) (re)absorption as a consequence of loss of TRPM6 channel function. |
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| MeSH term(s) | Biological Transport ; Calcium/blood ; Cell Membrane/metabolism ; Electrophysiological Phenomena ; Epithelial Cells/metabolism ; Female ; Follow-Up Studies ; HEK293 Cells ; Humans ; Hypocalcemia/diagnosis ; Hypocalcemia/genetics ; Infant ; Infant, Newborn ; Intestinal Absorption ; Intestinal Mucosa/metabolism ; Kidney/metabolism ; Magnesium/blood ; Magnesium/pharmacokinetics ; Magnesium Deficiency/congenital ; Male ; Mutation, Missense ; Renal Tubular Transport, Inborn Errors/diagnosis ; Renal Tubular Transport, Inborn Errors/genetics ; Retrospective Studies ; Sequence Analysis, DNA ; TRPM Cation Channels/genetics | |||||
| Chemical Substances | TRPM Cation Channels ; TRPM6 protein, human ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP) | |||||
| Language | English | |||||
| Publishing date | 2013-08-14 | |||||
| Publishing country | England | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1141470-4 | |||||
| ISSN | 1476-5438 ; 1018-4813 | |||||
| ISSN (online) | 1476-5438 | |||||
| ISSN | 1018-4813 | |||||
| DOI | 10.1038/ejhg.2013.178 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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