Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Am J Hum Genet. 2010 Feb 12;86(2):267-72. doi: 10.1016/j.ajhg.2010.01.006. Epub 2010 Feb 4.
The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization.
对影响磷酸盐稳态的罕见遗传疾病的分析导致了几种对肾脏调节磷酸盐稳态至关重要的蛋白质的鉴定；例如，成纤维细胞生长因子 23（FGF23），它抑制肾脏磷酸盐重吸收和 1,25-二羟维生素 D 合成。在这里，我们报告了受影响的四个家庭成员中存在假定的 ENPP1 基因（核苷酸焦磷酸酶/磷酸二酯酶）失活突变与低磷酸盐性佝偻病。我们提供的证据表明，除 PHEX、FGF23 和 DMP1 之外，ENPP1 是第四个基因，如果发生突变，会导致由 FGF23 水平升高引起的低磷酸盐性佝偻病。令人惊讶的是，先前已经在婴儿全身性动脉钙化症中描述了 ENPP1 失活突变，这表明存在一个迄今尚未明确的机制，该机制平衡了动脉钙化和骨矿化。
