title: Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density.
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.
authors.affiliation: Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8885, USA. berenice.gitomer@utsouthwestern.edu
authors.forename: Berenice Y
authors.initials: BY
authors.lastname: Reed
authors.forename: William L
authors.initials: WL
authors.lastname: Gitomer
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Heller
authors.forename: Ming Chue
authors.initials: MC
authors.lastname: Hsu
authors.forename: Martha
authors.initials: M
authors.lastname: Lemke
authors.forename: Paulette
authors.initials: P
authors.lastname: Padalino
authors.forename: Charles Y C
authors.initials: CY
authors.lastname: Pak
mesh_terms: D000042:Absorption; D000262:Adenylyl Cyclases / Q000235:genetics; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence / Q000235:genetics; D015519:Bone Density; D002118:Calcium / Q000652:urine*; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008159:Lumbar Vertebrae / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012995:Solubility; D013131:Spine / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D000262:Adenylyl Cyclases; D002118:Calcium