Whole exome sequencing investigation of UTR variants that may dictate CYP24A1 intracellular activity

Hypomorphic mutations in the CYP24A1 protein coding region causing persistently elevated active vitamin D metabolites have been observed in some cases of idiopathic infantile hypercalcemia (IIH) and adult onset nephrolithiasis. It is unclear why some cases present with superficial CYP24A1 mediated hypercalcemia but do not exhibit CYP24A1 mutations. Here we used next generation sequencing to investigate CYP24A1 mutations in a patient cohort with superficial CYP24A1 mediated hypercalcemia. We report several single nucleotide variants located in the CYP24A1 UTR. Our results provide a framework that can be used to better understand the molecular basis of pathogenesis in hypercalcaemic patients lacking CYP24A1 protein coding region abnormalities.

在部分特发性婴儿高钙血症（idiopathic infantile hypercalcemia, IIH）及成人起病肾石症病例中，已发现存在于细胞色素P450 24A1（CYP24A1）蛋白编码区的功能减低突变，该突变可导致活性维生素D代谢物持续升高。目前尚不清楚，为何部分临床表现为CYP24A1介导高钙血症的病例，却未检出CYP24A1编码区突变。本研究采用下一代测序（Next Generation Sequencing）技术，针对一组表现为CYP24A1介导高钙血症的患者队列开展CYP24A1突变分析。本研究报道了数种位于CYP24A1非翻译区（Untranslated Region, UTR）的单核苷酸变异。本研究结果可为解析无CYP24A1蛋白编码区异常的高钙血症患者的发病分子机制提供参考框架。