A Loss-of-Function Mutation in NaPi-IIa and Renal Fanconi's Syndrome

Two siblings from a consanguineous family who had autosomal recessive renal Fanconi's syndrome and hypophosphatemic rickets were found to have a homozygous in-frame duplication of 21 bp in SLC34A1, the gene that encodes the renal sodium–phosphate cotransporter NaPi-IIa. This mutation results in complete loss of function of the mutant NaPi-IIa, since the transporters fail to reach the plasma membrane. These findings show that disruption of human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function. Two siblings who had renal Fanconi's syndrome and rickets were found to have a mutation in SLC34A1, the gene that encodes the renal sodium̵1;phosphate cotransporter NaPi-IIa. These findings show that disruption of human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function. Renal phosphate handling occurs predominantly in the proximal tubule, where 70 to 80% of filtered phosphate is recovered. 1 Two principal phosphate transporters, NaPi-IIa and NaPi-IIc, have been identified on the apical membrane of the mammalian proximal tubule. 2 , 3 Although extensively studied in murine models, in which NaPi-IIa serves as the predominant mediator of renal phosphate reabsorption, 4 , 5 the importance of NaPi-IIa in regulating renal phosphate handling in humans remains controversial. To date, mutations in the SLC34A1 gene, which encodes NaPi-IIa, have not been found to cause any known human form of hereditary hypophosphatemic rickets or proximal tubulopathy. Sequence variants in . . .