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Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?

Gitelman’s syndrome (GS) and Bartter’s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature’s experiments, we found them to be a human model of endogenous...

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Autores principales: Calò, Lorenzo A, Davis, Paul A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460608/
https://www.ncbi.nlm.nih.gov/pubmed/32784543
http://dx.doi.org/10.3390/ijms21165660
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author Calò, Lorenzo A
Davis, Paul A
author_facet Calò, Lorenzo A
Davis, Paul A
author_sort Calò, Lorenzo A
collection PubMed
description Gitelman’s syndrome (GS) and Bartter’s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature’s experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine’s ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.
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spelling pubmed-74606082020-09-03 Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype? Calò, Lorenzo A Davis, Paul A Int J Mol Sci Review Gitelman’s syndrome (GS) and Bartter’s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature’s experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine’s ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system. MDPI 2020-08-07 /pmc/articles/PMC7460608/ /pubmed/32784543 http://dx.doi.org/10.3390/ijms21165660 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Calò, Lorenzo A
Davis, Paul A
Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?
title Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?
title_full Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?
title_fullStr Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?
title_full_unstemmed Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?
title_short Are the Clinical Presentations (Phenotypes) of Gitelman’s and Bartter’s Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their “pH” Enotype?
title_sort are the clinical presentations (phenotypes) of gitelman’s and bartter’s syndromes gene mutations driven by their effects on intracellular ph, their “ph” enotype?
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460608/
https://www.ncbi.nlm.nih.gov/pubmed/32784543
http://dx.doi.org/10.3390/ijms21165660
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