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Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant

Christianson syndrome (CS) is an X-linked neurogenetic disorder resulting from loss-of-function (LoF) mutations in SLC9A6, which encodes the endosomal Na(+)/H(+) exchanger 6 (NHE6). NHE6 regulates proton efflux from endosomes and, thus, participates in regulating cargo processing and trafficking. Lo...

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Autores principales: Ouyang, Qing, Joesch-Cohen, Lena, Mishra, Sasmita, Riaz, Hasib A., Schmidt, Michael, Morrow, Eric M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893231/
https://www.ncbi.nlm.nih.gov/pubmed/31676550
http://dx.doi.org/10.1523/ENEURO.0046-19.2019
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author Ouyang, Qing
Joesch-Cohen, Lena
Mishra, Sasmita
Riaz, Hasib A.
Schmidt, Michael
Morrow, Eric M.
author_facet Ouyang, Qing
Joesch-Cohen, Lena
Mishra, Sasmita
Riaz, Hasib A.
Schmidt, Michael
Morrow, Eric M.
author_sort Ouyang, Qing
collection PubMed
description Christianson syndrome (CS) is an X-linked neurogenetic disorder resulting from loss-of-function (LoF) mutations in SLC9A6, which encodes the endosomal Na(+)/H(+) exchanger 6 (NHE6). NHE6 regulates proton efflux from endosomes and, thus, participates in regulating cargo processing and trafficking. LoF mutations in NHE6 cause aberrant acidification of endosomes. While CS arises in males generally due to clear LoF mutations, other potentially hypomorphic variants have emerged, yet most of these variants have not been evaluated for functional effects, particularly in vivo. Here we characterize an SLC9A6 variant that has been previously reported in patients, yet now also appears in exome datasets of largely control individuals—c.25G>T, p.A9S. By heterologous expression in cell lines, we show that human NHE6A9S is expressed and localizes in a manner comparable to control NHE6. By genome editing, we generated the equivalent NHE6 mutation in mouse—p.A11S—and determined that male NHE6A11S mice have normal brain size at 6 months of age and do not show cerebellar degeneration or defective neuronal arborization. Neurons from male NHE6A11S mice also did not demonstrate an abnormality in intraendosomal pH compared with controls. These findings are in contrast to findings in NHE6-null mice previously reported and indicate that the NHE6A11S variant functions at a level equivalent to control NHE6 for many of the assays performed. These data stand in support of the population genetic data, which are also evaluated here, indicating that the A9S variant is unlikely to confer disease susceptibility with high penetrance.
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spelling pubmed-68932312019-12-05 Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant Ouyang, Qing Joesch-Cohen, Lena Mishra, Sasmita Riaz, Hasib A. Schmidt, Michael Morrow, Eric M. eNeuro New Research Christianson syndrome (CS) is an X-linked neurogenetic disorder resulting from loss-of-function (LoF) mutations in SLC9A6, which encodes the endosomal Na(+)/H(+) exchanger 6 (NHE6). NHE6 regulates proton efflux from endosomes and, thus, participates in regulating cargo processing and trafficking. LoF mutations in NHE6 cause aberrant acidification of endosomes. While CS arises in males generally due to clear LoF mutations, other potentially hypomorphic variants have emerged, yet most of these variants have not been evaluated for functional effects, particularly in vivo. Here we characterize an SLC9A6 variant that has been previously reported in patients, yet now also appears in exome datasets of largely control individuals—c.25G>T, p.A9S. By heterologous expression in cell lines, we show that human NHE6A9S is expressed and localizes in a manner comparable to control NHE6. By genome editing, we generated the equivalent NHE6 mutation in mouse—p.A11S—and determined that male NHE6A11S mice have normal brain size at 6 months of age and do not show cerebellar degeneration or defective neuronal arborization. Neurons from male NHE6A11S mice also did not demonstrate an abnormality in intraendosomal pH compared with controls. These findings are in contrast to findings in NHE6-null mice previously reported and indicate that the NHE6A11S variant functions at a level equivalent to control NHE6 for many of the assays performed. These data stand in support of the population genetic data, which are also evaluated here, indicating that the A9S variant is unlikely to confer disease susceptibility with high penetrance. Society for Neuroscience 2019-11-24 /pmc/articles/PMC6893231/ /pubmed/31676550 http://dx.doi.org/10.1523/ENEURO.0046-19.2019 Text en Copyright © 2019 Ouyang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Ouyang, Qing
Joesch-Cohen, Lena
Mishra, Sasmita
Riaz, Hasib A.
Schmidt, Michael
Morrow, Eric M.
Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant
title Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant
title_full Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant
title_fullStr Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant
title_full_unstemmed Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant
title_short Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant
title_sort functional assessment in vivo of the mouse homolog of the human ala-9-ser nhe6 variant
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893231/
https://www.ncbi.nlm.nih.gov/pubmed/31676550
http://dx.doi.org/10.1523/ENEURO.0046-19.2019
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