NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak
NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak
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DOI：
10.1038/sj.ki.5000437
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发表时间：
2006-06-01
影响因子：
19.6
通讯作者：
Bonnardeaux, A.
中科院分区：
文献类型：
--
作者：
Lapointe, J. -Y.;Tessier, J.;Bonnardeaux, A.
在一些高钙尿石症患者中发现肾磷酸盐重吸收减少伴轻度低磷酸盐血症（磷酸盐渗漏）。NPT 2a基因编码钠-磷酸盐协同转运蛋白，位于近端小管中，负责以限速方式回收大部分过滤的磷酸盐负荷。为了确定NPT 2a基因的遗传变异是否与98个多尿钙结石形成者家系中的磷酸盐渗漏和高钙尿有关，我们对28个先证者的整个cDNA编码区进行了测序，这些先证者的肾小管磷酸盐重吸收率（TmP/GFR）标准化为0.7mmol/l或更低。我们对整个队列中的每种遗传变异进行了基因型/表型相关性分析，并在非洲爪蟾卵母细胞中表达了NPT 2a变异RNA，以测试协同转运蛋白的功能。我们鉴定了编码区的几种变体，包括截短蛋白质N端胞质尾的框内21 bp缺失（91 del 7），以及其他非同义（A133 V和H568 Y）或同义的单核苷酸多态性。与野生型（wt）纯合子相比，NPT 2a变体杂合子携带者的TmP/GFR和尿钙排泄水平相似。H568 Y突变体的转运活性与野生型相同，而N-末端截短的版本和91 del 7和A133 V突变体呈现微小的动力学变化和表达水平的降低。虽然NPT 2a的遗传变异并不罕见，但在一个大的高钙尿石形成家系队列中，它们似乎与临床显著的肾磷酸盐或钙处理异常无关。
A decrease in renal phosphate reabsorption with mild hypophosphatemia (phosphate leak) is found in some hypercalciuric stone-formers. The NPT2a gene encodes a sodium-phosphate cotransporter, located in the proximal tubule, responsible for reclaiming most of the filtered phosphate load in a rate-limiting manner. To determine whether genetic variation of the NPT2a gene is associated with phosphate leak and hypercalciuria in a cohort of 98 pedigrees with multiple hypercalciuric stone-formers, we sequenced the entire cDNA coding region of 28 probands, whose tubular reabsorption of phosphate normalized for the glomerular filtration rate (TmP/GFR) was 0.7mmol/l or lower. We performed genotype/ phenotype correlations for each genetic variant in the entire cohort and expressed NPT2a variant RNAs in Xenopus laevis oocytes to test for cotransporter functionality. We identified several variants in the coding region including an in-frame 21 bp deletion truncating the N-terminal cytoplasmic tail of the protein (91del7), as well as other single-nucleotide polymorphisms that were non-synonymous (A133V and H568Y) or synonymous. Levels of TmP/GFR and urine calcium excretion were similar in heterozygote carriers of NPT2a variants compared to the wild-type (wt) homozygotes. The transport activity of the H568Y mutants was identical to the wt, whereas the N-terminal-truncated version and the 91del7 and A133V mutants presented minor kinetic changes and a reduction in the expression level. Although genetic variants of NPT2a are not rare, they do not seem to be associated with clinically significant renal phosphate or calcium handling anomalies in a large cohort of hypercalciuric stone-forming pedigrees.