Three People With Recurrent Nephrolithiasis and Heterozygous ABCC6 Mutations

Monogenic causes of nephrolithiasis and nephrocalcinosis are relatively common but underdiagnosed. Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease that causes progressive ectopic calcium phosphate deposits throughout the body. PXE results from homozygous mutations in the ATP-binding cassette subfamily C member 6 (ABCC6) gene, which encodes an ATP transporter that is predominantly expressed in the liver but also expressed in the kidney proximal tubule. ABCC6 transports ATP extracellularly, where ectonucleotide pyrophosphatase/phosphodiesterase 1 metabolizes ATP into AMP and pyrophosphate (PP_i), an inhibitor of calcium crystallization. Loss-of-function mutations in ABCC6 are associated with low serum PP_i levels, leading to ectopic calcifications. PXE is associated with an increased risk of nephrolithiasis, but it is currently unknown if heterozygotes are also at risk. Herein, we presented 3 patients with recurrent nephrolithiasis who had relatively unremarkable risk factors but were found to have heterozygous mutations in ABCC6-patient 1 c.1685T>C (p.Met562Thr); patient 2 c.933C>A (p.Phe311Leu); and patient 3 c.3413G>A (p.Arg1138Gln). We proposed that heterozygous ABCC6 mutations are an unrecognized risk factor for nephrolithiasis. Development of a clinical assay to measure urinary PP_i may help identify people at risk of nephrolithiasis, elucidate the underlying mechanisms of recurrent nephrolithiasis, and potentially identify a therapeutic target to reduce stone burden.