期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 29, 期 3, 页码 1041-1048出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2017080840
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资金
- Medical Research Council [MR/M012212/1]
- Kidney Research UK
- Kids Kidney Research
- Northern Counties Kidney Research Fund
- Newcastle upon Tyne Hospitals NHS Charity
- European Union, FP7 (European Consortium for High-Throughput Research in Rare Kidney Diseases (EURenOmics)) [2012-305608]
- John Moorhead Trust
- Swedish Research Council [2014-2516]
- Knut and Alice Wallenberg Foundation
- Sahlgrenska's University Hospital
- Inga Britt and Arne Lundgren Foundation
- Torsten Sderberg Foundation
- Novo Nordisk Foundation
- King Gustaf Vand Queen Victoria Freemason Foundation
- Swiss National Science Foundation [155959]
- European Union FP7 project EURenOmics
- MRC [MR/M012212/1] Funding Source: UKRI
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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