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Human kidney stone disease (KSD) causes significant morbidity and public health burden worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defects to complex interaction between genetic and environmental factors. However, the genetic defects causing KSD in the majority of affected families are still unknown. Here, we report the discovery of mutations of  SCN10A , encoding Na V 1.8 α subunit of voltage-gated sodium channel, in families with KSD. The region on chromosome 3 where  SCN10A  locates was initially identified in a large family with KSD by genome-wide linkage analysis and exome sequencing. Two mutations (p.N909K and p.K1809R) in the same allele of  SCN10A  co-segregated with KSD in the affected family. Additional mutation (p.V1149M) of  SCN10A  was identified in another affected family, strongly supporting the causal role of  SCN10A  for KSD. The amino acids at these three positions, N909, K1809, and V1149, are highly conserved in vertebrate evolution, indicating their structural and functional significances. Na V 1.8 α subunit mRNA and protein were found to express in human kidney tissues. The mutant proteins expressed in cultured cells were unstable and causing reduced current density as analyzed by whole-cell patch-clamp technique. Thus, loss-of-function mutations of  SCN10A  were associated with KSD in the families studied.

Loss-of-function mutations of SCN10A encoding NaV1.8 α subunit of voltage-gated sodium channel in patients with human kidney stone disease