Missense mutation in the sodium phosphate co-transporter slc34a1 impairs phosphate homeostasis
Missense mutation in the sodium phosphate co-transporter slc34a1 impairs phosphate homeostasis
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DOI：
10.1681/asn.2007121360
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发表时间：
2008-09-01
影响因子：
13.6
通讯作者：
Castellino, Francis J.
中科院分区：
文献类型：
--
作者：
Iwaki, Takayuki;Sandoval-Coopel, Mayra J.;Castellino, Francis J.
磷酸钠共转运蛋白Npt 2a和Npt 2c在磷酸盐稳态调节中起重要作用。Slc 34 a1是编码Npt 2a的基因，位于编码凝血因子XII（f12）的基因下游，在产生f12（-/-）小鼠时被无意中修饰。在本报告中，描述了这种修改的肾脏后果。组合的单等位基因突变体Slc 34 a1 m在外显子13中包含两个点突变：A499 V位于胞内环5，V528 M位于跨膜结构域11。除了预期的f12（-/-）表型凝血病外，双等位基因修饰（f12（-/-）/slc 34 a1（m/m））纯合子小鼠显示低磷酸盐血症、高钙血症、碱性磷酸酶水平升高、尿石症和肾积水。策略性交叉试验表明，肾脏相关病理仅与slc 34 a1（m）基因的常染色体隐性遗传有关，而不受同时发生的f12失活的影响。Npt 2a [V528 M]能在负鼠肾细胞中正常表达，而Npt 2a [A499 V]不能。这些结果表明，Npt 2a中的单个氨基酸取代可导致蛋白质向细胞膜的不适当易位、磷酸盐稳态的紊乱和肾钙化。SLC 34 A1基因的点突变是否会导致人类低磷酸盐血症和肾结石仍不清楚。
The sodium phosphate co-transporters Npt2a and Npt2c play important roles in the regulation of phosphate homeostasis. Slc34a1, the gene encoding Npt2a, resides downstream of the gene encoding coagulation factor XII (f12) and was inadvertently modified while generating f12(-/-) mice. In this report, the renal consequences of this modification are described. The combined single allelic mutant Slc34a1m contains two point mutations in exon 13: A499V is located in intracellular loop 5, and V528M is located in transmembrane domain 11. In addition to the expected coagulopathy of the f12(-/-) phenotype, mice homozygous for the double allelic modification (f12(-/-)/slc34a1(m/m)) displayed hypophosphatemia, hypercalcemia, elevated levels of alkaline phosphatase, urolithiasis, and hydronephrosis. Strategic crossbreedings demonstrated that the kidney-related pathology was associated only with autosomal recessive transmission of the slc34a1(m) gene and was not influenced by the simultaneous inactivation of f12. Npt2a[V528M] could be properly expressed in opossum kidney cells, but Npt2a[A499V] could not. These results suggest that a single amino acid substitution in Npt2a can lead to improper translocation of the protein to the cell membrane, disturbance of phosphate homeostasis, and renal calcification. Whether point mutations in the SLC34A1 gene can lead to hypophosphatemia and nephrolithiasis in humans remains unknown.