Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Basic Research
You have accessRestricted Access

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Daan Viering, Karl P. Schlingmann, Marguerite Hureaux, Tom Nijenhuis, Andrew Mallett, Melanie M.Y. Chan, André van Beek, Albertien M. van Eerde, Jean-Marie Coulibaly, Marion Vallet, Stéphane Decramer, Solenne Pelletier, Günter Klaus, Martin Kömhoff, Rolf Beetz, Chirag Patel, Mohan Shenoy, Eric J. Steenbergen, Glenn Anderson, Ernie M.H.F. Bongers, Carsten Bergmann, Daan Panneman, Richard J. Rodenburg, Robert Kleta, Pascal Houillier, Martin Konrad, Rosa Vargas-Poussou, Nine V.A.M. Knoers, Detlef Bockenhauer, Jeroen H.F. de Baaij and the Genomics England Research Consortium
JASN February 2022, 33 (2) 305-325; DOI: https://doi.org/10.1681/ASN.2021050596
Daan Viering
1Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Daan Viering
Karl P. Schlingmann
2Department of General Pediatrics, University Children’s Hospital, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Karl P. Schlingmann
Marguerite Hureaux
3Reference Center for Hereditary Kidney and Childhood Diseases (Maladies rénales héréditaires de l'enfant et de l'adulte [MARHEA]), Paris, France
4Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tom Nijenhuis
5Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew Mallett
6Department of Renal Medicine, Townsville University Hospital, Townsville, Australia
7Queensland Conjoint Renal Genetics Service – Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melanie M.Y. Chan
8Department of Renal Medicine, University College London, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Melanie M.Y. Chan
André van Beek
9Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for André van Beek
Albertien M. van Eerde
10Genetics Department, University Medical Center Utrecht, Utrecht, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean-Marie Coulibaly
11Service of Nephrology, Yves Le Foll Hospital, Saint Brieuc, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marion Vallet
12Department of Physiological Functional Investigations, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stéphane Decramer
13Pediatric Nephrology, Internal Medicine and Rheumatology, Southwest Renal Rare Diseases Centre (SORARE), University Children's Hospital, Toulouse, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Solenne Pelletier
14Department of Nephrology, University Hospital–Lyon Sud, Lyon, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Günter Klaus
15Kuratorium für Heimdialyse Pediatric Kidney Center, Marburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Kömhoff
16University Children's Hospital, Philipps-University, Marburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rolf Beetz
17Johannes Gutenberg Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Mainz, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chirag Patel
7Queensland Conjoint Renal Genetics Service – Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mohan Shenoy
18Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric J. Steenbergen
19Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glenn Anderson
20Department of Pathology, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ernie M.H.F. Bongers
21Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carsten Bergmann
22Limbach Genetics, Medizinische Genetik Mainz, Prof. Bergmann & Kollegen, Mainz, Germany
23Department of Medicine, Division of Nephrology, University Hospital Freiburg, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daan Panneman
24Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard J. Rodenburg
24Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert Kleta
8Department of Renal Medicine, University College London, London, United Kingdom
25Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Robert Kleta
Pascal Houillier
3Reference Center for Hereditary Kidney and Childhood Diseases (Maladies rénales héréditaires de l'enfant et de l'adulte [MARHEA]), Paris, France
26Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de Recherche Médicale (INSERM), Université de Paris, Centre National de la Recherche Scientifique (CNRS), Paris, France
27Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Konrad
2Department of General Pediatrics, University Children’s Hospital, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rosa Vargas-Poussou
3Reference Center for Hereditary Kidney and Childhood Diseases (Maladies rénales héréditaires de l'enfant et de l'adulte [MARHEA]), Paris, France
4Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France
26Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de Recherche Médicale (INSERM), Université de Paris, Centre National de la Recherche Scientifique (CNRS), Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Rosa Vargas-Poussou
Nine V.A.M. Knoers
28Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nine V.A.M. Knoers
Detlef Bockenhauer
8Department of Renal Medicine, University College London, London, United Kingdom
29Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Detlef Bockenhauer
Jeroen H.F. de Baaij
1Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jeroen H.F. de Baaij
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Visual Abstract

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint

Significance Statement

Biallelic pathogenic variants in SLC12A3, encoding the thiazide-sensitive sodium chloride cotransporter NCC, cause Gitelman syndrome. Gitelman patients suffer from hypokalemic alkalosis, hypomagnesemia, and salt wasting. A subset of Gitelman syndrome cases remains genetically unsolved. This paper describes the identification of pathogenic mitochondrial DNA (mtDNA) variants in the genes encoding the transfer RNAs for phenylalanine (MT-TF) and isoleucine (MT-TI) in 13 families with a Gitelman-like phenotype. Six families were additionally affected by progressive CKD. Mitochondrial dysfunction was demonstrated in patient-derived fibroblasts and linked to defective sodium reabsorption by NCC in vitro. These findings advocate for screening for mtDNA variants in unexplained Gitelman syndrome patients and influence genetic counseling of affected families. Furthermore, they provide insight into the physiology of renal sodium handling.

Abstract

Background Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl− cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown.

Methods We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport.

Results Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake.

Conclusion Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.

  • epithelial sodium transport
  • genetic renal disease
  • human genetics
  • Na transport
  • ion transport
  • mitochondria
  • Gitelman-s syndrome
  • blood pressure
  • chronic kidney disease
  • chronic kidney failure
  • Copyright © 2022 by the American Society of Nephrology
View Full Text
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 33 (2)
Journal of the American Society of Nephrology
Vol. 33, Issue 2
February 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
Daan Viering, Karl P. Schlingmann, Marguerite Hureaux, Tom Nijenhuis, Andrew Mallett, Melanie M.Y. Chan, André van Beek, Albertien M. van Eerde, Jean-Marie Coulibaly, Marion Vallet, Stéphane Decramer, Solenne Pelletier, Günter Klaus, Martin Kömhoff, Rolf Beetz, Chirag Patel, Mohan Shenoy, Eric J. Steenbergen, Glenn Anderson, Ernie M.H.F. Bongers, Carsten Bergmann, Daan Panneman, Richard J. Rodenburg, Robert Kleta, Pascal Houillier, Martin Konrad, Rosa Vargas-Poussou, Nine V.A.M. Knoers, Detlef Bockenhauer, Jeroen H.F. de Baaij, the Genomics England Research Consortium
JASN Feb 2022, 33 (2) 305-325; DOI: 10.1681/ASN.2021050596

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
Daan Viering, Karl P. Schlingmann, Marguerite Hureaux, Tom Nijenhuis, Andrew Mallett, Melanie M.Y. Chan, André van Beek, Albertien M. van Eerde, Jean-Marie Coulibaly, Marion Vallet, Stéphane Decramer, Solenne Pelletier, Günter Klaus, Martin Kömhoff, Rolf Beetz, Chirag Patel, Mohan Shenoy, Eric J. Steenbergen, Glenn Anderson, Ernie M.H.F. Bongers, Carsten Bergmann, Daan Panneman, Richard J. Rodenburg, Robert Kleta, Pascal Houillier, Martin Konrad, Rosa Vargas-Poussou, Nine V.A.M. Knoers, Detlef Bockenhauer, Jeroen H.F. de Baaij, the Genomics England Research Consortium
JASN Feb 2022, 33 (2) 305-325; DOI: 10.1681/ASN.2021050596
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Visual Abstract
    • Abstract
    • Methods
    • Results
    • Discussion
    • Disclosures
    • Funding
    • Acknowledgments
    • Supplemental Material
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Single-Cell Chromatin and Gene-Regulatory Dynamics of Mouse Nephron Progenitors
  • Myeloid CCR2 Promotes Atherosclerosis after AKI
  • Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease
Show more Basic Research

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • PubMed
  • Google Scholar

Keywords

  • epithelial sodium transport
  • genetic renal disease
  • human genetics
  • Na transport
  • ion transport
  • mitochondria
  • Gitelman-s syndrome
  • blood pressure
  • chronic kidney disease
  • chronic kidney failure

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals
  • Wolters Kluwer Partnership

© 2022 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire