Department of Pediatrics, University of Michigan, 1150 W. Medical Center Drive Drive, Ann Arbor, MI, USA.
Nephrol Dial Transplant. 2010 Sep;25(9):2970-6. doi: 10.1093/ndt/gfq088. Epub 2010 Feb 18.
Recessive mutations in the NPHS1 gene encoding nephrin account for approximately 40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons.
We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS.
We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (approximately 51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin.
Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatment.
编码足细胞裂孔隔膜蛋白（nephrin）的 NPHS1 基因的隐性突变约占先天性肾病综合征（CNS）患儿的 40%。CNS 是指出生后 90 天内发生的激素抵抗性肾病综合征（SRNS）。目前，已有超过 119 种不同的 NPHS1 突变被报道，影响大多数外显子。
我们对来自 62 个不同家系的 67 名 CNS 患儿进行了 NPHS1 的突变分析。
我们在一个世界性的 CNS 患儿队列中发现了 62 个家系中的 36 个家系（58%）存在双等位基因突变，证实了约有一半的 CNS 是由 NPHS1 突变引起的。在 26 个家系中，突变是纯合的，在 10 个家系中，突变是复合杂合的。在另外 8 个家系的 9 名患者中，仅检测到一个杂合突变。我们共检测到 37 种不同的突变。其中 19 种（约 51.4%）为新突变，包括 11 种错义突变、4 种剪接位点突变、3 种无义突变和 1 种小缺失。在另一位晚发的患者中，我们发现了另外两种新突变，其中一种突变影响了 nephrin 的糖基化位点。
我们的数据将已知突变谱扩大了 17.6%。令人惊讶的是，在两个患有 NPHS1 纯合新突变 L587R 的同胞中，只有一个在 90 天前出现肾病综合征，而另一个直到 2 岁时才发病。这两个同胞在接受激素治疗后都出现了部分缓解的意外情况。
