# Three People With Recurrent Nephrolithiasis and Heterozygous ABCC6 Mutations

## TL;DR

This paper reports three patients with kidney stones who had mutations in the ABCC6 gene, suggesting these mutations may be a new risk factor for kidney stones.

## Contribution

The study identifies heterozygous ABCC6 mutations as a potential novel risk factor for nephrolithiasis.

## Key findings

- Three patients with recurrent nephrolithiasis had heterozygous ABCC6 mutations.
- Heterozygous ABCC6 mutations may be an unrecognized cause of kidney stones.
- Measuring urinary pyrophosphate could help identify and treat at-risk individuals.

## Abstract

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 (PPi), an inhibitor of calcium crystallization. Loss-of-function mutations in ABCC6 are associated with low serum PPi 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 PPi 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.