Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant
Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant
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DOI：
10.1038/ki.2008.650
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发表时间：
2009-04-01
影响因子：
19.6
通讯作者：
Antignac, Corinne
中科院分区：
文献类型：
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作者：
Machuca, Eduardo;Hummel, Aurelie;Antignac, Corinne
编码podocin的NPHS2基因突变是儿童期常染色体隐性遗传类固醇抵抗性肾病综合征（NS）的主要原因。在致病性NPHS2突变与p.R229Q变异杂合的患者中，已经描述了成人发病的类固醇耐药NS。为了确定携带p.R229Q变异的患者的频率和表型，我们对对免疫抑制治疗无反应或移植后无复发的455个家庭（546例患者）的NPHS2完整编码区进行了测序。在受影响的欧洲人中，p.R229Q等位基因的频率明显高于对照组。来自27个家族（11个来自欧洲，14个来自南美）的36例患者为p.R229Q变异的复合杂合子和1个致病突变。这些患者的NS和终末期肾病的发病时间明显晚于两种致病突变的患者。在119例18岁以后出现的NS患者中，发现18例患者有一个致病突变和p.R229Q，但没有人有两个致病突变。我们的研究表明，p.R229Q的复合杂合性与成人发病的类固醇抵抗性NS有关，主要发生在欧洲和南美的患者中。建议在这些患者中筛查p.R229Q变体，并对携带该变体的患者进行进一步的NPHS2突变分析。
Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients, along with further NPHS2 mutation analysis in those carrying the variant.