Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome
Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome
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DOI：
10.1136/jmg.2009.076166
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发表时间：
2010-07-01
影响因子：
4
通讯作者：
Antignac, Corinne
中科院分区：
文献类型：
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作者：
Boyer, Olivia;Benoit, Genevieve;Antignac, Corinne
最近在早发性肾病综合征（NS）和弥漫性系膜硬化（DMS）患者中发现了编码磷脂酶C epsilon 1 （PLC31）的PLCE1基因突变。此外，还报道了2例PLCE1突变与局灶节段性肾小球硬化（FSGS）和晚期NS发病相关的病例。方法为了更好地评估与PLCE1突变相关的表型谱，对139例类固醇耐药NS患者（95例家族病例，属于68个家族，44例散发病例）进行了突变分析，这些患者的中位年龄为23.0个月（范围0-373）。结果33%（8/24）的DMS患者存在纯合或复合杂合突变。无NPHS2突变的FSGS患者中有8%（6/78）存在PLCE1突变。其中9个是新的突变。没有观察到明显的基因型-表型相关性，在DMS和FSGS中都检测到截断或错义突变，导致类似的肾脏进化。令人惊讶的是，三个未受影响和不相关的个体也被发现在他们各自的家庭中携带纯合突变。结论PLCE1是DMS的主要基因，在未发生NPHS2突变的FSGS病例中发生突变的比例不容忽视。虽然19个候选基因（其他16个PLC基因，BRAF， IQGAP1和NPHS1）的其他变异未被发现，但推测其他修饰基因或环境因素可能在携带PLCE1突变的个体中观察到的肾脏表型变异性中起作用。在向患者提供遗传咨询时，需要考虑到这一观察结果。
Background Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLC31) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported.Method In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373).Results Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families.Conclusion PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF, IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.