Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels.
CALHM1 is a plasma membrane voltage-gated Ca2+-permeable ion channel that controls amyloid-β (Aβ) metabolism and is potentially involved in the onset of Alzheimer's disease (AD). Recently, Rubio-Moscardo et al. (PLoS One (2013) 8: e74203) reported the identification of two CALHM1 variants, G330...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4227689?pdf=render |
| _version_ | 1818270859783045120 |
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| author | Valérie Vingtdeux Jessica E Tanis Pallavi Chandakkar Haitian Zhao Ute Dreses-Werringloer Fabien Campagne J Kevin Foskett Philippe Marambaud |
| author_facet | Valérie Vingtdeux Jessica E Tanis Pallavi Chandakkar Haitian Zhao Ute Dreses-Werringloer Fabien Campagne J Kevin Foskett Philippe Marambaud |
| author_sort | Valérie Vingtdeux |
| collection | DOAJ |
| description | CALHM1 is a plasma membrane voltage-gated Ca2+-permeable ion channel that controls amyloid-β (Aβ) metabolism and is potentially involved in the onset of Alzheimer's disease (AD). Recently, Rubio-Moscardo et al. (PLoS One (2013) 8: e74203) reported the identification of two CALHM1 variants, G330D and R154H, in early-onset AD (EOAD) patients. The authors provided evidence that these two human variants were rare and resulted in a complete loss of CALHM1 function. Recent publicly available large-scale exome sequencing data confirmed that R154H is a rare CALHM1 variant (minor allele frequency (MAF) = 0.015%), but that G330D is not (MAF = 3.5% in an African American cohort). Here, we show that both CALHM1 variants exhibited gating and permeation properties indistinguishable from wild-type CALHM1 when expressed in Xenopus oocytes. While there was also no effect of the G330D mutation on Ca2+ uptake by CALHM1 in transfected mammalian cells, the R154H mutation was associated with defects in the control by CALHM1 of both Ca2+ uptake and Aβ levels in this cell system. Together, our data show that the frequent CALHM1 G330D variant has no obvious functional consequences and is therefore unlikely to contribute to EOAD. Our data also demonstrate that the rare R154H variant interferes with CALHM1 control of cytosolic Ca2+ and Aβ accumulation. While these results strengthen the notion that CALHM1 influences Aβ metabolism, further investigation will be required to determine whether CALHM1 R154H, or other natural variants in CALHM1, is/are associated with EOAD. |
| first_indexed | 2024-12-12T21:16:59Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T21:16:59Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-dcc9cf9544d840f3a0ff8b8499002e312022-12-22T00:11:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01911e11248410.1371/journal.pone.0112484Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels.Valérie VingtdeuxJessica E TanisPallavi ChandakkarHaitian ZhaoUte Dreses-WerringloerFabien CampagneJ Kevin FoskettPhilippe MarambaudCALHM1 is a plasma membrane voltage-gated Ca2+-permeable ion channel that controls amyloid-β (Aβ) metabolism and is potentially involved in the onset of Alzheimer's disease (AD). Recently, Rubio-Moscardo et al. (PLoS One (2013) 8: e74203) reported the identification of two CALHM1 variants, G330D and R154H, in early-onset AD (EOAD) patients. The authors provided evidence that these two human variants were rare and resulted in a complete loss of CALHM1 function. Recent publicly available large-scale exome sequencing data confirmed that R154H is a rare CALHM1 variant (minor allele frequency (MAF) = 0.015%), but that G330D is not (MAF = 3.5% in an African American cohort). Here, we show that both CALHM1 variants exhibited gating and permeation properties indistinguishable from wild-type CALHM1 when expressed in Xenopus oocytes. While there was also no effect of the G330D mutation on Ca2+ uptake by CALHM1 in transfected mammalian cells, the R154H mutation was associated with defects in the control by CALHM1 of both Ca2+ uptake and Aβ levels in this cell system. Together, our data show that the frequent CALHM1 G330D variant has no obvious functional consequences and is therefore unlikely to contribute to EOAD. Our data also demonstrate that the rare R154H variant interferes with CALHM1 control of cytosolic Ca2+ and Aβ accumulation. While these results strengthen the notion that CALHM1 influences Aβ metabolism, further investigation will be required to determine whether CALHM1 R154H, or other natural variants in CALHM1, is/are associated with EOAD.http://europepmc.org/articles/PMC4227689?pdf=render |
| spellingShingle | Valérie Vingtdeux Jessica E Tanis Pallavi Chandakkar Haitian Zhao Ute Dreses-Werringloer Fabien Campagne J Kevin Foskett Philippe Marambaud Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels. PLoS ONE |
| title | Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels. |
| title_full | Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels. |
| title_fullStr | Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels. |
| title_full_unstemmed | Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels. |
| title_short | Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels. |
| title_sort | effect of the calhm1 g330d and r154h human variants on the control of cytosolic ca2 and aβ levels |
| url | http://europepmc.org/articles/PMC4227689?pdf=render |
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