Mice defective in Trpm6 show embryonic mortality and neural tube defects

Walder, Roxanne Y.; Yang, Baoli; Stokes, John B.; Kirby, Patricia; Cao, Xiao; Shi, Pengju; Searby, Charles; Husted, Russell F.; Sheffield, Val C.

doi:10.1093/hmg/ddp392

Cited by 93 publications

(90 citation statements)

References 44 publications

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“…Heterozygous TRPM6 þ / À mice exhibit mild hypomagnesemia under a normal diet as an indication of a milder phenotype associated with the loss of one TRPM6 allele. 33,34 Still, the observed difference in serum Mg 2 þ values in these mice is rather low although significant. 33,34 Moreover, the heterozygous deletion of TRPM6 results in unaffected Mg 2 þ urinary excretion when compared with WT under normal Mg 2 þ diet.…”

Section: Discussionmentioning

confidence: 79%

“…33,34 Still, the observed difference in serum Mg 2 þ values in these mice is rather low although significant. 33,34 Moreover, the heterozygous deletion of TRPM6 results in unaffected Mg 2 þ urinary excretion when compared with WT under normal Mg 2 þ diet. 33 In contrast to this situation in mice, measured serum Mg 2 þ values from parents in our study are normal (data not shown), indicating that heterozygous humans are asymptomatic and have no significant change in Mg 2 þ metabolism, not supporting the idea of a milder phenotype in humans.…”

Section: Discussionmentioning

confidence: 79%

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New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 79%

New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia

et al. 2013

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“…I am not aware of a TRPM6 knockout mouse model that is not an embryonic lethal. 68 The human patient data suggest hypocalcemia and possibly hypercalciuria are caused by parathyroid gland failure induced by hypomagnesemia. When there is hypercalciuria, the risk of developing kidney stones will be higher.…”

Section: Questions and Answersmentioning

confidence: 99%

Lecture

Hou

2012

Organogenesis

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“…Those that survive display massive neural tube closure defects. 103 Interestingly, plasma Mg 2ϩ levels are lower in TRPM6 ϩ/Ϫ as compared with TRPM6 ϩ/ϩ mice. In contrast to HSH, high-Mg 2ϩ diet does not prevent mortality in TRPM6-null embryos.…”

Section: Role Of Trpm6 Channels In Renal Magnesium Homeostasismentioning

confidence: 97%

“…101,102 The recent description of a TRPM6-deficient mouse model adds yet another level of complexity. 103 The absence of TRPM6 gives rise to a different phenotype in mice than in humans. In contrast to previous expectations, the majority of TRPM6 Ϫ/Ϫ mice die at approximately day 12.5.…”

Section: Role Of Trpm6 Channels In Renal Magnesium Homeostasismentioning

confidence: 99%

Renal TRPathies

Dietrich¹,

Chubanov²,

Gudermann³

2010

Journal of the American Society of Nephrology

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One key function of the kidneys is the ultrafiltration of plasma by glomeruli to dispose of metabolic end products, excess electrolytes, and water. A vast array of ion channels and transporters are critical for filtration, secretion, and resorption of electrolytes to maintain homeostasis. In recent years, investigations have focused on several members of the large transient receptor potential (TRP) family of ion channels, because mutations in genes encoding members of three different TRP ion channel subfamilies have been linked to human kidney diseases. 1 Mutations in PKD1 (encoding TRPP1) and PKD2 (coding for TRPP2) occur at high frequency in individuals with autosomal dominant polycystic kidney disease. 2,3 The latter mutations and the pathophysiology of polycystic kidney disease are not discussed further in this overview because the topic has been covered by numerous insightful review articles. 4 -7 Missense and nonsense mutations in the gene coding for TRPC6 segregate with autosomal dominant FSGS, a kidney disease that leads to progressive renal failure. 8,9 Loss-of-function mutations in TRPM6 are also associated with hypomagnesemia with secondary hypocalcemia (HSH), a rare autosomal recessive disorder. 10 -12 The involvement of TRP channel mutations in hereditary kidney disease has shed new light on the molecular pathogenesis of renal failure and significantly enhanced our appreciation of the physiologic roles of TRP channels on tubular function. In this review, we focus exclusively on TRPC6 and TRPM6. TRPC6 AND PODOCYTE FUNCTIONTRPC6 is a nonselective cation channel and one of the seven members of the classical transient receptor potential (TRPC) family, which can be divided into subfamilies on the basis of amino acid similarity. Whereas TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approximately 64% amino acid identity. TRPC3, TRPC6, and TRPC7 form a structural and functional subfamily displaying 65 to 78% identity at the amino acid level and share a common activator, diacylglycerol (DAG). 13 DAG is produced by phospholipase C isozymes activated after agonist binding to appropriate receptors, such as the interaction of angiotensin II (AngII) with AT 1 receptors.Like all TRPC family members, TRPC6 harbors an invariant sequence, the TRP box (containing the amino acid sequence EWKFAR), in its C-terminal tail as well as three ankyrin repeats in the N-terminus (Figure 1, A and B). The predicted transmembrane topology is similar to that of other TRP channels with intracellular N-and C-termini, six membrane-spanning helices (S1 through S6), and a presumed pore-forming loop (P) between S5 and S6 (Figure 1, A and B). As deduced from Northern blot analyses, TRPC6 channels are most prominently expressed in lung tissues, 14 where they ABSTRACTMany ion channels and transporters are involved in the filtration, secretion, and resorption of electrolytes by the kidney. In recent years, the superfamily of transient receptor potential (TRP) ion channels have received deserved attention because mutated TRP ch...

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Mice defective in Trpm6 show embryonic mortality and neural tube defects

Cited by 93 publications

References 44 publications

New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia

New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia

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Renal TRPathies

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