Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.
Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/398083a269454e2e838e54531e91aaa4 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:398083a269454e2e838e54531e91aaa4 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:398083a269454e2e838e54531e91aaa42021-11-18T07:59:24ZAutosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.1932-620310.1371/journal.pone.0055412https://doaj.org/article/398083a269454e2e838e54531e91aaa42013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23383183/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5(682P/+)) and homozygous (Trpv5(682P/682P)) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P) mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3) concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+) and Trpv5(682P/682P) mice consistent with a trafficking defect. In addition, Trpv5(682P/682P) mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K), consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate that the TRPV5 S682P mutant is functionally significant and study of HCALC1, a novel model for autosomal dominant hypercalciuria, may help further our understanding of renal calcium reabsorption and hypercalciuria.Nellie Y LohLiz BentleyHenrik DimkeSjoerd VerkaartPaolo TammaroCaroline M GorvinMichael J StechmanBushra N AhmadFadil M HannanSian E PiretHolly EvansIlaria BellantuonoTertius A HoughWilliam D FraserJoost G J HoenderopFrances M AshcroftSteve D M BrownRené J M BindelsRoger D CoxRajesh V ThakkerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e55412 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Nellie Y Loh Liz Bentley Henrik Dimke Sjoerd Verkaart Paolo Tammaro Caroline M Gorvin Michael J Stechman Bushra N Ahmad Fadil M Hannan Sian E Piret Holly Evans Ilaria Bellantuono Tertius A Hough William D Fraser Joost G J Hoenderop Frances M Ashcroft Steve D M Brown René J M Bindels Roger D Cox Rajesh V Thakker Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5. |
| description |
Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5(682P/+)) and homozygous (Trpv5(682P/682P)) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P) mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3) concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+) and Trpv5(682P/682P) mice consistent with a trafficking defect. In addition, Trpv5(682P/682P) mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K), consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate that the TRPV5 S682P mutant is functionally significant and study of HCALC1, a novel model for autosomal dominant hypercalciuria, may help further our understanding of renal calcium reabsorption and hypercalciuria. |
| format |
article |
| author |
Nellie Y Loh Liz Bentley Henrik Dimke Sjoerd Verkaart Paolo Tammaro Caroline M Gorvin Michael J Stechman Bushra N Ahmad Fadil M Hannan Sian E Piret Holly Evans Ilaria Bellantuono Tertius A Hough William D Fraser Joost G J Hoenderop Frances M Ashcroft Steve D M Brown René J M Bindels Roger D Cox Rajesh V Thakker |
| author_facet |
Nellie Y Loh Liz Bentley Henrik Dimke Sjoerd Verkaart Paolo Tammaro Caroline M Gorvin Michael J Stechman Bushra N Ahmad Fadil M Hannan Sian E Piret Holly Evans Ilaria Bellantuono Tertius A Hough William D Fraser Joost G J Hoenderop Frances M Ashcroft Steve D M Brown René J M Bindels Roger D Cox Rajesh V Thakker |
| author_sort |
Nellie Y Loh |
| title |
Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5. |
| title_short |
Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5. |
| title_full |
Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5. |
| title_fullStr |
Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5. |
| title_full_unstemmed |
Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5. |
| title_sort |
autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, trpv5. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/398083a269454e2e838e54531e91aaa4 |
| work_keys_str_mv |
AT nellieyloh autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT lizbentley autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT henrikdimke autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT sjoerdverkaart autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT paolotammaro autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT carolinemgorvin autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT michaeljstechman autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT bushranahmad autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT fadilmhannan autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT sianepiret autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT hollyevans autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT ilariabellantuono autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT tertiusahough autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT williamdfraser autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT joostgjhoenderop autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT francesmashcroft autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT stevedmbrown autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT renejmbindels autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT rogerdcox autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 AT rajeshvthakker autosomaldominanthypercalciuriainamousemodelduetoamutationoftheepithelialcalciumchanneltrpv5 |
| _version_ |
1718422657596129280 |