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Submitted on December 30, 2005
Accepted on July 12, 2006
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710; Department of Medicine, Division of Endocrinology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
* To whom correspondence should be addressed. E-mail: mecons{at}iupui.edu.
Context: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia and rickets/osteomalacia with increased serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] resulting in hypercalciuria.
Objective: To determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc (NaPi-IIc), are responsible for the occurrence of HHRH.
Design: Mutation detection of exons and adjacent introns in the SLC34A3 gene by DNA sequencing.
Setting: An academic research laboratory and medical center.
Patients or Other Participants: Members of two unrelated families with HHRH.
Intervention(s): None.
Main Outcome Measure(s): DNA sequence variations in the SLC34A3 gene.
Results: Two affected siblings in one family were homozygous for a 101-bp deletion in intron 9. Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes. An unrelated individual with HHRH was a compound heterozygote for an 85-bp deletion in intron 10 and a G-to-A substitution at the last nucleotide in exon 7. The intron 9 deletion (and likely the other two mutations) identified in this study cause aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences.
Conclusion: HHRH is caused by biallelic mutations in the SLC34A3 gene. Haplotype analysis suggests that the two intron 9 deletions arose independently. The identification of three independent intronic deletions in a rare disorder suggests that the SLC34A3 gene may be susceptible to unequal crossing over due to sequence misalignment during meiosis.
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  G. Jaureguiberry, T. O. Carpenter, S. Forman, H. Juppner, and C. Bergwitz A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc Am J Physiol Renal Physiol, August 1, 2008; 295(2): F371 - F379. [Abstract] [Full Text] [PDF]
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M. Levi Novel NaPi-2c mutations that cause mistargeting of NaPi-2c protein and uncoupling of Na-Pi cotransport cause HHRH Am J Physiol Renal Physiol, August 1, 2008; 295(2): F369 - F370. [Full Text] [PDF]
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L. V. Virkki, J. Biber, H. Murer, and I. C. Forster Phosphate transporters: a tale of two solute carrier families Am J Physiol Renal Physiol, September 1, 2007; 293(3): F643 - F654. [Abstract] [Full Text] [PDF]
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