Human Molecular Genetics Advance Access originally published online on August 18, 2009
Human Molecular Genetics 2009 18(22):4367-4375; doi:10.1093/hmg/ddp392
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Published by Oxford University Press 2009
Mice defective in Trpm6 show embryonic mortality and neural tube defects
1 Department of Pediatrics, 2 Department of Obstetrics and Gynecology, 3 Department of Internal Medicine, 4 Department of Pathology, 5 Howard Hughes Medical Institute and 6 Department of Veterans Affairs Medical Center, University of Iowa, Iowa City, IA, USA
* To whom correspondence should be addressed at: E300 GH, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Tel: +1 3193564409; Fax: +1 3193562999; Email: john-stokes{at}uiowa.edu
Received May 17, 2009; Accepted August 13, 2009
The syndrome of hypomagnesemia with secondary hypocalcemia is caused by defective TRPM6. This protein is an ion channel that also contains a kinase in its C-terminus. It is usually diagnosed in childhood and, without treatment with supplemental Mg, affected children suffer from mental retardation, seizures and retarded development. We developed a mouse lacking Trpm6 in order to understand in greater detail the function of this protein. In contrast to our expectations, Trpm6–/– mice almost never survived to weaning. Many mice died by embryonic day 12.5. Most that survived to term had neural tube defects consisting of both exencephaly and spina bifida occulta, an unusual combination. Feeding dams a high Mg diet marginally improved offspring survival to weaning. The few Trpm6–/– mice that survived were fertile but matings between Trpm6–/– mice produced no viable pregnancies. Trpm6+/– mice had normal electrolytes except for modestly low plasma [Mg]. In addition, some Trpm6+/– mice died prematurely. Absence of Trpm6 produces an apparently different phenotype in mice than in humans. The presence of neural tube defects identifies a previously unsuspected role of Trpm6 in effecting neural tube closure. This genetic defect produces one of very few mouse models of spina bifida occulta. These results point to a critical role of Trpm6 in development and suggest an important role in neural tube closure.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.