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Acidosis and Deafness in Patients with Recessive Mutations in FOXI1.

Authors
  • Enerbäck, Sven1
  • Nilsson, Daniel2
  • Edwards, Noel3
  • Heglind, Mikael2
  • Alkanderi, Sumaya3
  • Ashton, Emma4
  • Deeb, Asma5
  • Kokash, Feras E B6
  • Bakhsh, Abdul R A6
  • Van't Hoff, William7
  • Walsh, Stephen B8
  • D'Arco, Felice6
  • Daryadel, Arezoo9, 10
  • Bourgeois, Soline9, 10
  • Wagner, Carsten A9, 10
  • Kleta, Robert7, 8
  • Bockenhauer, Detlef7, 8
  • Sayer, John A3
  • 1 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; [email protected] , (Sweden)
  • 2 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. , (Sweden)
  • 3 Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom. , (United Kingdom)
  • 4 North East Thames Regional Genetic Service Laboratories, London, United Kingdom. , (United Kingdom)
  • 5 Pediatric Services, Mafraq Hospital, Abu Dhabi, United Arab Emirates. , (United Arab Emirates)
  • 6 College of Medicine, Gulf Medical University, Ajman, United Arab Emirates. , (United Arab Emirates)
  • 7 Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, United Kingdom. , (United Kingdom)
  • 8 University College London Centre for Nephrology, London, United Kingdom. , (United Kingdom)
  • 9 Institute of Physiology, University of Zürich, Zurich, Switzerland; and. , (Switzerland)
  • 10 National Center for Competence in Research, National Center in Competence in Research Kidney.CH, Zurich, Switzerland. , (Switzerland)
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology
Publication Date
Mar 01, 2018
Volume
29
Issue
3
Pages
1041–1048
Identifiers
DOI: 10.1681/ASN.2017080840
PMID: 29242249
Source
Medline
Keywords
License
Unknown

Abstract

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

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