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 acidbase 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
