Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.

H Jorge Baluarte, Clemens Bergwitz, Harald Jüppner, Hang Lee, Craig F Munns, Lars Sävendahl, Martin Konrad, Bernd Hoppe, Shoji Ichikawa, Thomas O Carpenter, David A Hanley, Karl Insogna, Dov Tiosano, Michael A Levine, Debayan Dasgupta, Shamir Tuchman, Dionisios Chrysis, Michaela Gessner, Joanna Lazier, Andrew Biggin, Marco Janner, Karl-Peter Schlingmann, Amita Sharma, Peter J Simm, Yuwen Li, Monica Reyes, Mark J Wee

Journal: Journal of the American Society of Nephrology : JASN 2014;25(10):2366-75

PMID: 24700880

Abstract

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.

Copyright © 2014 by the American Society of Nephrology.

Address: Endocrine Unit, and.; Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Discipline of Pediatrics and Child Health, University of Sydney, Sydney, Australia;; Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;; Department of General Pediatrics, University Children's Hospital, Münster, Germany;; Division of Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Bern, Germany;; Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Westmead, New South Wales, Australia;; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada;; Division of Pediatric Nephrology, Department of Pediatrics, University Hospital, Köln, Germany;; Division of Endocrinology, Department of Pediatrics, University of Patras Medical School, Patras, Greece;; Division of Pediatric Nephrology, Children's National Medical Center, The George Washington University School of Medicine, Washington, District of Columbia;; University of Pennsylvania, School of Medicine, Division of Pediatric Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;; Division of Pediatric Endocrinology, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel;; Division of Endocrinology, Department of Medicine and.; Departments of Medicine, Community Health Sciences, and Oncology, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada;; Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut;; Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana;; Pediatric Endocrinology Unit, Department of Women's and Children´s Health, Karolinska Institutet, Stockholm, Sweden; and.; Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.; Endocrine Unit, and Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;; Endocrine Unit, and [email protected].
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