Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density
Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density
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DOI：
10.1210/jc.87.4.1476
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发表时间：
2002-04-01
影响因子：
5.8
通讯作者：
Pak, CYC
中科院分区：
文献类型：
--
作者：
Reed, BY;Gitomer, WL;Pak, CYC
吸收性高钙尿症（AH）是一种肾结石形成疾病，经常并发骨质流失。先前，我们将AH遗传形式的基因座定位于染色体1q23.3-q24。我们已经测序了一个假定的基因（随后被其他人证明是同源的大鼠可溶性腺苷酸环化酶基因）在这一地区在12个无关的高加索AH患者。在可溶性腺苷酸环化酶人类同源基因中鉴定了18个碱基替换。在另外3-68名无关AH患者和19-132名正常受试者中进一步评估了所有序列变异，并鉴定了1个额外的碱基替换。六个确定的序列变异发生在AH人群中的频率增加，并跟踪AH家族中的AH表型。计算的比值比显示，发生任何4个碱基替换与AH估计风险增加2.2- 3.5倍相关（P < 0.02）。此外，1个或多个基底改变与L2-L4椎体骨密度降低相关。对AH连锁区间内的其他3个基因的序列分析表明，AH和正常人群之间的序列变异分布没有差异。这是第一次描述与AH相关的特定基因缺陷。
Absorptive hyperealciuria (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.