Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.
Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.
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DOI：
10.1053/j.ajkd.2008.07.041
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Aronson PS
中科院分区：
文献类型：
--
作者：
Monico CG;Weinstein A;Jiang Z;Rohlinger AL;Cogal AG;Bjornson BB;Olson JB;Bergstralh EJ;Milliner DS;Aronson PS
尿草酸盐是草酸钙结石的主要危险因素。显着的高草酸尿症由两个独立基因座 AGXT 和 GRHPR 的突变引起，这两个基因座分别是原发性高草酸尿症 (PH) 1 型和 2 型的原因。对 Slc26a6 (−/−) 无效小鼠的研究揭示了高草酸尿症、高草酸血症和草酸钙尿石症的表型，从而提出了 SLC26A6 突变可能导致或改变人类高草酸尿症的假设。横断面病例对照。病例是从国际原发性高草酸尿登记处招募的。对照 DNA 样本来自一群自认为健康状况良好的成年受试者。病例中的 PH1、PH2、非 PH1/PH2 基因型。 SLC26A6 变体的纯合性或复合杂合性。爪蟾卵母细胞草酸转运的功能表达。总共有 80 个 PH1、6 个 PH2、8 个非 PH1/PH2 和 96 个对照样本可用于 SLC26A6 筛选。仅在一个非 PH1/PH2 谱系中检测到一种罕见的变异 c.487C>T (p.Pro163Ser)，但该变异未能与高草酸尿症分离，并且爪蟾卵母细胞中草酸盐转运的功能研究显示没有转运缺陷。在非 PH1/PH2 中没有专门鉴定出其他罕见变异。在对照和病例中还检测到了另外六种错义变异。其中，c.616G>A (p.Val206Met) 最常见 (11%)，草酸盐转运减少 30%。为了测试 p.Val206Met 作为高草酸尿症的潜在调节剂，我们将筛选范围扩大到 PH1 和 PH2。该变异的杂合性不影响该人群的血浆或尿液草酸盐。我们没有足够数量的病例来确定 p.Val206Met 的纯合性是否可能显着影响尿草酸盐。在这个非 PH1/PH2 队列中，SLC26A6 被有效排除为疾病基因。总而言之，我们的研究首次鉴定并表征了高草酸尿症中的 SLC26A6 变异。表型和功能分析排除了已识别的变异对草酸盐排泄的显着影响。
Urinary oxalate is a major risk factor for calcium oxalate stones. Marked hyperoxaluria arises from mutations in two separate loci, AGXT and GRHPR, the causes of primary hyperoxaluria (PH) types 1 and 2, respectively. Studies of null Slc26a6 (−/−) mice have revealed a phenotype of hyperoxaluria, hyperoxalemia and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify hyperoxaluria in humans. Cross-sectional, case-control. Cases were recruited from the International Primary Hyperoxaluria Registry. Control DNA samples were from a pool of adult subjects who identified themselves as being in good health. PH1, PH2, non-PH1/PH2 genotypes in cases. Homozygosity or compound heterozygosity for SLC26A6 variants. Functional expression of oxalate transport in Xenopus oocytes. A total of 80 PH1, 6 PH2, 8 non-PH1/PH2 and 96 control samples were available for SLC26A6 screening. A rare variant, c.487C>T (p.Pro163Ser) was detected solely in one non-PH1/PH2 pedigree but this variant failed to segregate with hyperoxaluria, and functional studies of oxalate transport in Xenopus oocytes revealed no transport defect. No other rare variant was identified specifically in non-PH1/PH2. Six additional missense variants were detected in controls and in cases. Of these, c.616G>A (p.Val206Met) was most common (11%), and showed a 30% reduction in oxalate transport. To test p.Val206Met as a potential modifier of hyperoxaluria, we extended screening to PH1 and PH2. Heterozygosity for this variant did not affect plasma or urine oxalate in this population. We did not have a sufficient number of cases to determine whether homozygosity for p.Val206Met might significantly affect urine oxalate. SLC26A6 was effectively ruled out as the disease gene in this non-PH1/PH2 cohort. Taken together, our studies are the first to identify and characterize SLC26A6 variants in hyperoxaluria. Phenotypic and functional analysis excluded a significant effect of identified variants on oxalate excretion.
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影响因子：
4.4
作者：
Lohi, H;Kujala, M;Kere, J
通讯作者：
Kere, J
DOI：
10.1152/ajpgi.00338.2001
发表时间：
2002-03-01
影响因子：
4.5
作者：
Wang, ZH;Petrovic, S;Soleimani, M
通讯作者：
Soleimani, M
影响因子：
56.9
作者：
TRUDEAU, MC;WARMKE, JW;ROBERTSON, GA
通讯作者：
ROBERTSON, GA
影响因子：
19.6
作者：
Monico, CG;Persson, M;Milliner, DS
通讯作者：
Milliner, DS
影响因子：
6.6
作者：
Monga, Manoj;Macias, Brandon;Hargens, Alan
通讯作者：
Hargens, Alan