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 NaV1.8 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. NaV1.8 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.
Scientific reports. 2018 Jul 11*** epublish ***
Choochai Nettuwakul, Oranud Praditsap, Nunghathai Sawasdee, Nanyawan Rungroj, Katesirin Ruamyod, Wattana B Watanapa, Mutita Junking, Sittideth Sangnual, Suchai Sritippayawan, Boonyarit Cheunsuchon, Duangporn Chuawattana, Santi Rojsatapong, Wipada Chaowagul, Sulayman D Dib-Hajj, Stephen G Waxman, Pa-Thai Yenchitsomanus
Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand., Division of Molecular Genetics, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand., Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand., Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand., Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand., Department of Medicine, Sappasithiprasong Hospital, Ubon Ratchathani, 34000, Thailand., Department of Neurology & The Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, 06516, USA., Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand. .