NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.
NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.
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DOI：
10.1172/jci16242
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发表时间：
2002-12
期刊：
影响因子：
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通讯作者：
H. Tsukaguchi;A. Sudhakar;T. C. Le;Trang-Tiffany Nguyen;Jun Yao;Joshua A. Schwimmer;A. Schachter;E. Poch;P. Abreu;G. Appel;A. B. Pereira;R. Kalluri;M. Pollak
中科院分区：
文献类型：
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作者：
H. Tsukaguchi;A. Sudhakar;T. C. Le;Trang-Tiffany Nguyen;Jun Yao;Joshua A. Schwimmer;A. Schachter;E. Poch;P. Abreu;G. Appel;A. B. Pereira;R. Kalluri;M. Pollak
编码podocin的NPHS2基因突变已在儿童发病的局灶性和节段性肾小球硬化（FSGS）中被发现。NPHS2在成人疾病中的作用尚不明确。我们研究了30个有明显常染色体隐性遗传的FSGS家族和91个原发性FSGS个体。我们筛选了家族成员的NPHS2突变。NPHS2突变似乎与其中9个家族的疾病有关。在6个家族中，受影响的个体为非保守性R229Q氨基酸取代的复合杂合子。在对照人群中，R229Q变异的等位基因频率为3.6%。在这些家庭中，R229Q是在两个疾病相关的NPHS2等位基因之一上发现的唯一突变。我们使用体外翻译的podocin和纯化的nephrin来研究R229Q对它们相互作用的影响，发现nephrin与R229Q podocin的结合减少。这些数据表明，这种共同的多态性有助于FSGS的发展。携带R229Q突变的染色体具有一个共同的单倍型，定义了大约0.2 mb的区域。R229Q似乎与第二个突变体NPHS2等位基因相关，从而增强了对FSGS的易感性。鉴定R229Q突变可能具有临床重要性，因为nphs2相关疾病似乎定义了对皮质类固醇无反应的FSGS患者亚组。
Mutations in NPHS2, encoding podocin, have been identified in childhood onset focal and segmental glomerulosclerosis (FSGS). The role of NPHS2 in adult disease is less well defined. We studied 30 families with FSGS and apparent autosomal recessive inheritance and 91 individuals with primary FSGS. We screened family members for NPHS2 mutations. NPHS2 mutations appeared to be responsible for disease in nine of these families. In six families, the affected individuals were compound heterozygotes for a nonconservative R229Q amino acid substitution. This R229Q variant has an allele frequency of 3.6% in a control population. In these families, R229Q was the only mutation identified on one of the two disease-associated NPHS2 alleles. We used in vitro-translated podocin and purified nephrin to investigate the effect of R229Q on their interaction and found decreased nephrin binding to the R229Q podocin. These data suggest that this common polymorphism contributes to the development of FSGS. Chromosomes bearing the R229Q mutation share a common haplotype defining an approximately 0.2-Mb region. R229Q appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.