Nephrotic syndrome in the first year of life:: Two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2)
Nephrotic syndrome in the first year of life:: Two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2)
复制标题
DOI：
10.1542/peds.2006-2164
复制
发表时间：
2007-04-01
期刊：
影响因子：
8
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Hinkes, Bernward G.;Mucha, Bettina;Hildebrandt, Friedhelm
目标. NPHS 1、NPHS 2、WT 1和LAMB 2基因中的每一个突变都与肾病综合征有关，在生命的第一年表现出来。在肾病综合征患儿中，这些基因的致病突变在出生后第一年出现的相对频率尚不清楚。因此，我们分析了所有4个基因联合在一个大的欧洲队列的89名儿童从80个家庭表现在第一年的生活和特点的肾病综合征的基因型/表型相关性。我们对NPHS 1、NPHS 2和WT 1的相关外显子8和9进行了直接外显子测序，而LAMB 2基因通过酶错配切割进行了筛选。我们在66.3%（53/80）的家族中检测到致病突变（NPHS 1，NPHS 2，WT 1和LAMB 2：分别为22.5%，37.5%，3.8%和2.5%）。有84.8%的先天性肾病综合征（0-3个月）和44.1%的婴儿期肾病综合征（4-12个月）的家系可由突变解释。在先天性肾病综合征（39.1%）和婴儿肾病综合征（35.3%）家系中，NPHS 2突变是最常见的肾病综合征病因，而NPHS 1突变仅见于先天性肾病综合征患者。在45名尝试类固醇治疗的儿童中，只有1名患者获得了持久的反应。在这45名接受治疗的儿童中，28名有致病突变，28名儿童中没有一人对治疗有反应。第一，三分之二的肾病综合征表现在生命的第一年，可以解释的突变只有4个基因（NPHS 1，NPHS 2，WT 1，或LAMB 2）。第二，NPHS 1突变仅发生在先天性肾病综合征中。第三，在4个基因中的任何一个中具有致病突变的婴儿对类固醇治疗没有反应;因此，可以避免不必要的治疗尝试。第四，在早发性肾病综合征中很可能存在其他未知基因突变。
OBJECTIVES. Mutations in each of the NPHS1, NPHS2, WT1, and LAMB2 genes have been implicated in nephrotic syndrome, manifesting in the first year of life. The relative frequency of causative mutations in these genes in children with nephrotic syndrome manifesting in the first year of life is unknown. Therefore, we analyzed all 4 of the genes jointly in a large European cohort of 89 children from 80 families with nephrotic syndrome manifesting in the first year of life and characterized genotype/phenotype correlations.METHODS. We performed direct exon sequencing of NPHS1, NPHS2, and the relevant exons 8 and 9 of WT1, whereas the LAMB2 gene was screened by enzymatic mismatches cleavage.RESULTS. We detected disease-causing mutations in 66.3% (53 of 80) families ( NPHS1, NPHS2, WT1, and LAMB2: 22.5%, 37.5%, 3.8%, and 2.5%, respectively). As many as 84.8% of families with congenital onset (0-3 months) and 44.1% with infantile onset (4-12 months) of nephrotic syndrome were explained by mutations. NPHS2 mutations were the most frequent cause of nephrotic syndrome among both families with congenital nephrotic syndrome (39.1%) and infantile nephrotic syndrome (35.3%), whereas NPHS1 mutations were solely found in patients with congenital onset. Of 45 children in whom steroid treatment was attempted, only 1 patient achieved a lasting response. Of these 45 treated children, 28 had causative mutations, and none of the 28 responded to treatment.CONCLUSIONS. First, two thirds of nephrotic syndrome manifesting in the first year of life can be explained by mutations in 4 genes only ( NPHS1, NPHS2, WT1, or LAMB2). Second, NPHS1 mutations occur in congenital nephrotic syndrome only. Third, infants with causative mutations in any of the 4 genes do not respond to steroid treatment; therefore, unnecessary treatment attempts can be avoided. Fourth, there are most likely additional unknown genes mutated in early-onset nephrotic syndrome.