title: Mice defective in Trpm6 show embryonic mortality and neural tube defects.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Roxanne Y
authors.initials: RY
authors.lastname: Walder
authors.forename: Baoli
authors.initials: B
authors.lastname: Yang
authors.forename: John B
authors.initials: JB
authors.lastname: Stokes
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Kirby
authors.forename: Xiao
authors.initials: X
authors.lastname: Cao
authors.forename: Peijun
authors.initials: P
authors.lastname: Shi
authors.forename: Charles C
authors.initials: CC
authors.lastname: Searby
authors.forename: Russell F
authors.initials: RF
authors.lastname: Husted
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008274:Magnesium / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054259:Neural Tube / Q000254:growth & development / Q000378:metabolism; D009436:Neural Tube Defects / Q000196:embryology* / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C530168:Trpm6 protein, mouse; D008274:Magnesium
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