Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density

Berenice Y. Reed, William L. Gitomer, Howard J. Heller, Chue Hsu Ming, Martha Lemke, Paulette Padalino, Charles Y C Pak

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

Absorptive hypercalciuria (AH) is a kidney stone-forming condition frequently complicated by bone loss. Previously, we mapped the locus for an inherited form of AH to chromosome 1q23.3-q24. We have sequenced a putative gene (subsequently shown by others to be homologous with the rat soluble adenylate cyclase gene) in this region in 12 unrelated Caucasian AH patients. Eighteen base substitutions were identified in the soluble adenylate cyclase human homolog gene. All sequence variations were further evaluated in 3-68 additional unrelated AH patients and 19-132 normal subjects, and 1 additional base substitution was identified. Six of the identified sequence variations occurred with increased frequency in the AH population and tracked with the AH phenotype in AH families. Calculated odds ratios showed that the occurrence of any 4 of these individual base substitutions was associated with a 2.2- to 3.5-fold increase in estimated risk for AH (P < 0.02). In addition, 1 or more base changes was associated with a lower L2-L4 vertebral bone density. Sequence analysis of 3 other genes within the AH linkage interval showed no difference in the distribution of sequence variations between AH and normal populations. This is the first description of a specific gene defect associated with AH.

Original languageEnglish (US)
Pages (from-to)1476-1485
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume87
Issue number4
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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