Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting
Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting
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DOI：
10.1007/s00240-019-01116-2
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发表时间：
2019-12-01
期刊：
影响因子：
3.1
通讯作者：
Halbritter, Jan
中科院分区：
文献类型：
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作者：
Schoenauer, Ria;Petzold, Friederike;Halbritter, Jan
SLC34A3功能缺失突变代表了一种独特的肾脏磷酸盐消耗障碍的既定原因，称为遗传性低磷血症性软骨病伴高钙尿(HHRH)。SLC34A3编码肾脏磷酸盐转运蛋白NaPi2c，表达于近端肾小管尖刷缘。P.Ser192Leu的替换是欧洲HHRH患者中最常见的基因变化之一，但从未在临床或细胞水平上进行过系统评估。对一例32岁女性的同源c.575C>；T，p Ser192Leu替换进行了鉴定，使我们能够更全面地评估这种错义变异的影响。临床上，患者表现为肾脏磷酸盐消耗和肾脏钙化，无任何骨异常。有害的SLC34A3变异的杂合子携带者先前被描述为含有增加的肾结石形成和肾脏钙化的风险。因此，我们检查了P.Ser192Leu变异在我们的成人肾结石队列中的频率，并将结果与先前发表的P.Ser192Leu单等位基因和双等位基因P.Ser192Leu变化的临床结果进行了比较。在细胞水平上，P.Ser192Leu突变的转运蛋白在不同的细胞系统中定位于质膜，但在非洲爪哇卵母细胞中过度表达时，会导致无机磷的转运活性显著降低。尽管异位细胞系统的功能降低，P.Ser192Leu的临床后果可能看起来相对轻微，至少在我们的指标患者中是这样，在临床实践中可能会被忽略。
Loss-of-function mutations of SLC34A3 represent an established cause of a distinct renal phosphate wasting disorder termed hereditary hypophosphatemic rickets with hypercalciuria (HHRH). SLC34A3 encodes the renal phosphate transporter NaPi2c expressed at the apical brush border of proximal renal tubules. Substitution of p.Ser192Leu is one of the most frequent genetic changes among HHRH patients in Europe, but has never been systematically evaluated, clinically or on a cellular level. Identification of a 32-year-old female with a homozgyous c.575C>T, p.Ser192Leu substitution enabled a more comprehensive assessment of the impact of this missense variant. Clinically, the patient showed renal phosphate wasting and nephrocalcinosis without any bone abnormalities. Heterozygous carriers of deleterious SLC34A3 variants were previously described to harbor an increased risk of kidney stone formation and renal calcification. We hence examined the frequency of p.Ser192Leu variants in our adult kidney stone cohort and compared the results to clinical findings of previously published cases of both mono- and biallelic p.Ser192Leu changes. On a cellular level, p.Ser192Leu-mutated transporters localize to the plasma membrane in different cellular systems, but lead to significantly reduced transport activity of inorganic phosphate upon overexpression in Xenopus oocytes. Despite the reduced function in ectopic cellular systems, the clinical consequences of p.Ser192Leu may appear relatively mild, at least in our index patient, and can potentially be missed in clinical practice.