title: Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria.
abstract: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia, variable degrees of rickets/osteomalacia, and hypercalciuria secondary to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. HHRH is caused by mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc. A 6-1/2-year-old female presented with a history of nephrolithiasis. Her metabolic evaluation revealed increased 24-hour urine calcium excretion with high serum calcium, low intact parathyroid hormone (PTH), and elevated 1,25(OH)2D. In addition, the patient had low to low-normal serum phosphorus with high urine phosphorus. The patient had normal stature; without rachitic or boney deformities or a history of fractures. Genetic analysis of SLC34A3 revealed the patient to be a compound heterozygote for a novel single base pair deletion in exon 12 (c.1304delG) and 30-base pair deletion in intron 6 (g.1440-1469del). The single-base pair mutation causes a frameshift, which results in premature stop codon. The intronic deletion is likely caused by misalignment of the 4-basepair homologous repeats and results in the truncation of an already small intron to 63bp, which would impair proper RNA splicing of the intron. This is the fourth unique intronic deletion identified in patients with HHRH, suggesting the frequent occurrence of sequence misalignments in SLC34A3 and the importance of screening introns in patients with HHRH.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: ichikawa@iu.edu.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Division of Pediatric Nephrology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Shamir
authors.initials: S
authors.lastname: Tuchman
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Leah R
authors.initials: LR
authors.lastname: Padgett
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Amie K
authors.initials: AK
authors.lastname: Gray
authors.affiliation: Division of Pediatric Nephrology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: H Jorge
authors.initials: HJ
authors.lastname: Baluarte
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
mesh_terms: D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D003710:Demography; D053098:Familial Hypophosphatemic Rickets / Q000150:complications* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053565:Hypercalciuria / Q000150:complications* / Q000235:genetics*; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D017384:Sequence Deletion / Q000235:genetics*; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
chemical_list: C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc
keywords: Deletion; HHRH; Hypercalciuria; Hypophosphatemia; Intron; Nephrolithiasis