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Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

Lookup NU author(s): Dr Noel Edwards, Sumaya Alkanderi, Professor John Sayer

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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.


Publication metadata

Author(s): Enerb├Ąck S, Nilsson D, Edwards N, Heglind M, Alkanderi S, Ashton E, Deeb A, Kokash FEB, Bakhsh ARA, Van'tHoff W, Walsh SB, D'Arco F, Daryadel A, Bourgeois S, Wagner CA, Kleta R, Bockenhauer D, Sayer JA

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2018

Volume: 29

Issue: 3

Pages: 1041-1048

Print publication date: 01/03/2018

Online publication date: 14/12/2017

Acceptance date: 14/12/2017

Date deposited: 08/01/2018

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology

URL: https://doi.org/10.1681/ASN.2017080840

DOI: 10.1681/ASN.2017080840

PubMed id: 29242249


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