Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria.
BACKGROUND
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)(2)D] resulting in hypercalciuria.


OBJECTIVE
Our objective was to determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate cotransporter type IIc, are responsible for the occurrence of HHRH.


METHODS
Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center.


METHODS
Members of two unrelated families with HHRH participated in the study.


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 causes aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences.


CONCLUSIONS
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 deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis.
Ichikawa
Shoji
S
Department of Medicine, Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 459, Indianapolis, IN 46202-5121, USA.
Sorenson
Andrea H
AH
Imel
Erik A
EA
Friedman
Nancy E
NE
Gertner
Joseph M
JM
Econs
Michael J
MJ
D001483:Base Sequence; D002118:Calcium / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D017353:Gene Deletion; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics* / Q000652:urine; D007223:Infant; D007438:Introns; D007669:Kidney Calculi / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics*
C493562:SLC34A3 protein, human; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D002118:Calcium