Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis.

TitleExome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis.
Publication TypeJournal Article
Year of Publication2014
AuthorsRajagopal, A, Braslavsky, D, Lu, JT, Kleppe, S, Clément, F, Cassinelli, H, Liu, DS, Liern, JMiguel, Vallejo, G, Bergadá, I, Gibbs, RA, Campeau, PM, Lee, BH
JournalJ Clin Endocrinol Metab
Volume99
Issue11
PaginationE2451-6
Date Published2014 Nov
ISSN1945-7197
KeywordsChild, Child, Preschool, DNA Mutational Analysis, Exome, Female, Humans, Hypercalcemia, Hypercalciuria, Hypophosphatemia, Male, Mutation, Nephrocalcinosis, Parathyroid Hormone, Pedigree, Phenotype, Sodium-Phosphate Cotransporter Proteins, Type IIa
Abstract

CONTEXT: Two Argentinean siblings (a boy and a girl) from a nonconsanguineous family presented with hypercalcemia, hypercalciuria, hypophosphatemia, low parathyroid hormone (PTH), and nephrocalcinosis.

OBJECTIVE: The goal of this study was to identify genetic causes of the clinical findings in the two siblings.

DESIGN: Whole exome sequencing was performed to identify disease-causing mutations in the youngest sibling, and a candidate variant was screened in other family members by Sanger sequencing. In vitro experiments were conducted to determine the effects of the mutation that was identified.

PATIENTS AND OTHER PARTICIPANTS: Affected siblings (2 y.o. female and 10 y.o male) and their parents were included in the study. Informed consent was obtained for genetic studies.

RESULTS: A novel homozygous mutation in the gene encoding the renal sodium-dependent phosphate transporter SLC34A1 was identified in both siblings (c.1484G>A, p.Arg495His). In vitro studies showed that the p.Arg495His mutation resulted in decreased phosphate uptake when compared to wild-type SLC34A1.

CONCLUSIONS: The homozygous G>A transition that results in the substitution of histidine for arginine at position 495 of the renal sodium-dependent phosphate transporter, SLC34A1, is involved in disease pathogenesis in these patients. Our report of the second family with two mutated SLC34A1 alleles expands the known phenotype of this rare condition.

DOI10.1210/jc.2014-1517
Alternate JournalJ. Clin. Endocrinol. Metab.
PubMed ID25050900
PubMed Central IDPMC4223446
Grant ListCA125123 / CA / NCI NIH HHS / United States
HD070394 / HD / NICHD NIH HHS / United States
5T32DK060445-10 / DK / NIDDK NIH HHS / United States
AI036211 / AI / NIAID NIH HHS / United States
HD024064 / HD / NICHD NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
P30 AI036211 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
S10 RR024574 / RR / NCRR NIH HHS / United States
T32 DK060445 / DK / NIDDK NIH HHS / United States
P01 HD070394 / HD / NICHD NIH HHS / United States
RR024574 / RR / NCRR NIH HHS / United States