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Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting

Lookup NU author(s): Professor John SayerORCiD, Dr Andreas Werner



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019, The Author(s). Loss-of-function mutations of SLC34A3 represent an established cause of a distinct renal phosphate wasting disorder termed hereditary hypophosphatemic rickets with hypercalciuria (HHRH). SLC34A3 encodes the renal phosphate transporter NaPi2c expressed at the apical brush border of proximal renal tubules. Substitution of p.Ser192Leu is one of the most frequent genetic changes among HHRH patients in Europe, but has never been systematically evaluated, clinically or on a cellular level. Identification of a 32-year-old female with a homozgyous c.575C>T, p.Ser192Leu substitution enabled a more comprehensive assessment of the impact of this missense variant. Clinically, the patient showed renal phosphate wasting and nephrocalcinosis without any bone abnormalities. Heterozygous carriers of deleterious SLC34A3 variants were previously described to harbor an increased risk of kidney stone formation and renal calcification. We hence examined the frequency of p.Ser192Leu variants in our adult kidney stone cohort and compared the results to clinical findings of previously published cases of both mono- and biallelic p.Ser192Leu changes. On a cellular level, p.Ser192Leu-mutated transporters localize to the plasma membrane in different cellular systems, but lead to significantly reduced transport activity of inorganic phosphate upon overexpression in Xenopus oocytes. Despite the reduced function in ectopic cellular systems, the clinical consequences of p.Ser192Leu may appear relatively mild, at least in our index patient, and can potentially be missed in clinical practice.

Publication metadata

Author(s): Schonauer R, Petzold F, Lucinescu W, Seidel A, Muller L, Neuber S, Bergmann C, Sayer JA, Werner A, Halbritter J

Publication type: Article

Publication status: Published

Journal: Urolithiasis

Year: 2019

Volume: 47

Pages: 511-519

Print publication date: 01/12/2019

Online publication date: 23/02/2019

Acceptance date: 07/02/2019

Date deposited: 11/03/2019

ISSN (print): 2194-7228

ISSN (electronic): 2194-7236

Publisher: Springer Verlag


DOI: 10.1007/s00240-019-01116-2


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Funder referenceFunder name
14.06Northern Counties Kidney Research Fund
HA 6908/2-1
Wellcome Trust