Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.
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.
Endocrine Unit, and.
Debayan
D
Dasgupta
Endocrine Unit, and.
Mark J
MJ
Wee
Endocrine Unit, and.
Monica
M
Reyes
Endocrine Unit, and.
Yuwen
Y
Li
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;
Peter J
PJ
Simm
Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
Amita
A
Sharma
Department of General Pediatrics, University Children's Hospital, Münster, Germany;
Karl-Peter
KP
Schlingmann
Division of Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Bern, Germany;
Marco
M
Janner
Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Westmead, New South Wales, Australia;
Andrew
A
Biggin
Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada;
Joanna
J
Lazier
Division of Pediatric Nephrology, Department of Pediatrics, University Hospital, Köln, Germany;
Michaela
M
Gessner
Division of Endocrinology, Department of Pediatrics, University of Patras Medical School, Patras, Greece;
Dionisios
D
Chrysis
Division of Pediatric Nephrology, Children's National Medical Center, The George Washington University School of Medicine, Washington, District of Columbia;
Shamir
S
Tuchman
University of Pennsylvania, School of Medicine, Division of Pediatric Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
H Jorge
HJ
Baluarte
Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;
Michael A
MA
Levine
Division of Pediatric Endocrinology, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel;
Dov
D
Tiosano
Division of Endocrinology, Department of Medicine and.
Karl
K
Insogna
Departments of Medicine, Community Health Sciences, and Oncology, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada;
David A
DA
Hanley
Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut;
Thomas O
TO
Carpenter
Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana;
Shoji
S
Ichikawa
Division of Pediatric Nephrology, Department of Pediatrics, University Hospital, Köln, Germany;
Bernd
B
Hoppe
Department of General Pediatrics, University Children's Hospital, Münster, Germany;
Martin
M
Konrad
Pediatric Endocrinology Unit, Department of Women's and Children´s Health, Karolinska Institutet, Stockholm, Sweden; and.
Lars
L
Sävendahl
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;
Craig F
CF
Munns
Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.
Hang
H
Lee
Endocrine Unit, and Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
Harald
H
Jüppner
Endocrine Unit, and cbergwitz@partners.org.
Clemens
C
Bergwitz
D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007669:Kidney Calculi / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009397:Nephrocalcinosis / Q000235:genetics*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc