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Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

Journal article
Authors Sven Enerbäck
Daniel Nilsson
N. Edwards
Mikael Heglind
S. Alkanderi
E. Ashton
A. Deeb
F. E. B. Kokash
A. R. A. Bakhsh
W. van't Hoff
S. B. Walsh
F. D'Arco
A. Daryadel
S. Bourgeois
C. A. Wagner
R. Kleta
D. Bockenhauer
J. A. Sayer
Published in Journal of the American Society of Nephrology
Volume 29
Issue 3
Pages 1041-1048
ISSN 1046-6673
Publication year 2018
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 1041-1048
Language en
Keywords renal tubular-acidosis, transcription factor foxi1, crystal-structure, inner-ear, dna, proteins, complex, nephropathy, expression, exchanger, Urology & Nephrology
Subject categories Urology and andrology

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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