Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis
Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis
复制标题
DOI：
10.1038/ki.2009.381
复制
发表时间：
2009-12-01
影响因子：
19.6
通讯作者：
Torra, Roser
中科院分区：
文献类型：
--
作者：
Santin, Sheila;Garcia-Maset, Rafael;Torra, Roser
NPHS 1基因突变导致芬兰型先天性肾病综合征，在出生后3个月内出现。最近，NPHS 1突变也被确定在儿童期发病的类固醇耐药肾病综合征和轻度病程，但其在成人局灶节段性肾小球硬化症的作用仍然未知。在这里，我们开发了一个计算机评分矩阵，以评估致病性的氨基酸取代使用野生型和突变氨基酸之间的生物物理和生物化学差异，氨基酸残基的直系同源物的进化保守性，并定义域，与上下文信息的添加。对来自89个无关家族的97例患者进行了突变分析，其中52例在18岁后出现类固醇耐药肾病综合征。在5例家族性和7例散发性病例中发现了复合杂合或纯合NPHS 1突变，其中1例患者发病时27岁。使用该计算机模拟方法将置换分为“重度”或“轻度”。我们的研究结果表明，与至少有一个“轻度”突变的患者相比，具有两个“严重”突变的患者更早发病。在成人发病的局灶节段性肾小球硬化症患者中发现的突变表明，NPHS 1分析可以考虑在较晚发病的患者中进行。Kidney International（2009）76，1268-1276; doi：10.1038/ki.2009.381; 2009年10月7日在线发表
Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wildtype and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease. Kidney International (2009) 76, 1268-1276; doi:10.1038/ki.2009.381; published online 7 October 2009