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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.

Hypertension is the most important modifiable risk factor for death worldwide. Finding novel model mechanisms for blood-pressure (BP) regulation is an important goal and Mendelian syndromes have been very helpful in that regard. Pseudohypoparathyroidism type 1B (PHP1B) is an example in which affected individuals are invariably hypertensive for unknown reasons. We encountered a 48 year-old woman with severe, five-drug-resistant, hypertension. Her father and two aunts were also severely hypertensive. Her two young sons have developed drug-dependent hypertension before age 20 years. We measured 24-h ambulatory blood pressure and excluded all known secondary causes. However, the proband’s sons and their grandfather have the PHP1B phenotype, while our index patient and her two hypertensive aunts do not. The blood pressure phenotype in this pedigree suggested autosomal dominant inheritance. The Syntaxin 16 (STX16) gene encodes a snare protein and mutations cause PHP1B. Mutated STX16 causes methylation defects of Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS), a G protein regulator. Since GNAS is an imprinted gene, only inheritance from the mother causes the PHP1B phenotype. Subsequently, we sequenced STX16 in our kindred. We found a heterozygous deletion involving exons 5 and 6. We were also able to show complete loss of methylation in GNAS exon 1A. All hypertensive persons in our kindred have the STX16 mutation and are hypertensive. However, only those with maternal inheritance show the PHP1B phenotype. The methylation target region influenced by STX16 encompasses 7 genes. Our candidate is endothelin-3 encoded by EDN3 . Our data separate the hypertension-PHP1B phenotypes. We imply separate mechanisms are involved. We suggest new targets of blood pressure-raising relevance.