Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2
Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2
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DOI：
10.1093/ndt/gfr419
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发表时间：
2012-03-01
影响因子：
6.1
通讯作者：
Holtzman, Eliezer J.
中科院分区：
文献类型：
--
作者：
Dinour, Dganit;Gray, Nicola K.;Holtzman, Eliezer J.
背景血清尿酸（UA）升高与痛风、高血压、心血管和肾脏疾病有关。遗传性肾性低尿酸血症1型（RHUC 1）是由肾小管尿酸转运蛋白URAT 1突变引起的，可并发肾结石和运动诱发的急性肾功能衰竭（EIARF）。我们最近发现另一种尿酸转运蛋白GLUT 9的功能缺失纯合突变可导致一种严重的遗传性肾性低尿酸血症，并伴有类似的并发症（RHUC 2）。两个无关的家庭与肾性低尿酸血症的临床特点。提取DNA并对分别编码URAT 1和GLUT 9的SLC 22 A12和SLC 2A 9进行测序。通过对非洲爪蟾卵母细胞的转运研究，对GLUT 9突变的功能进行了评估，并通过分子模拟研究了这些突变的结构特征和影响。发现了两种新的纯合GLUT 9错义突变：R171 C和T125 M。4例纯合子受试者的平均血清UA水平为0.15 +/- 0.06 mg/dL，UA排泄分数为89- 150%。受影响的受试者均未发生肾结石、EIARF或任何其他并发症。运输试验表明，这两种突变蛋白质的运输UA的能力显着降低。建模显示R171 C和T125 M突变均位于胞质和细胞外区域之间转运UA的内部通道内。这是第二个报告的肾性低尿酸血症引起的纯合子GLUT 9突变。我们的研究结果证实了GLUT 9在UA转运中的关键作用，并强调了RHUC 1和RHUC 2之间的相似性和差异。
Background. Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2).Methods. Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations.Results. Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 +/- 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions.Conclusions. This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.