Division of Gastroenterology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Canada.
J Med Genet. 2012 Feb;49(2):138-44. doi: 10.1136/jmedgenet-2011-100544. Epub 2011 Dec 29.
Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.
The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.
Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.
This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
Alagille 综合征（ALGS）是一种显性多系统疾病，94%的患者是由 Jagged1（JAG1）配体突变引起的，<1%的患者是由 NOTCH2 受体突变引起的。迄今为止，仅报道了两个 NOTCH2 家族。本研究假设在没有 JAG1 突变的具有 ALGS 临床特征的患者中存在其他 NOTCH2 突变。
该研究筛选了一组具有 ALGS 临床特征的 JAG1 阴性个体，这些特征提示或诊断为 ALGS，以寻找 NOTCH2 突变。
鉴定出 8 名具有 NOVEL NOTCH2 突变（6 个错义突变、1 个剪接突变和 1 个无义突变）的个体。这 3 名患者符合 ALGS 的经典标准，而 5 名患者仅具有部分特征。这些突变分布在蛋白的细胞外（N=5）和细胞内结构域（N=3）。对 4 个错义突变、1 个无义突变和 1 个剪接突变进行功能分析，证明这些蛋白的 Notch 信号转导减少。具有 NOTCH2 突变的个体表现出受影响系统的高度可变表达性，与 JAG1 个体相似。NOTCH2 先证者的肝脏受累是普遍的，他们与 JAG1 患者一样，具有相似的眼部和肾脏异常发生率。NOTCH2 组的心脏受累趋势较低（60%对 JAG1 组的 100%）。与 JAG1 阳性队列相比，NOTCH2（+）先证者的椎骨异常（10%）和面部特征（20%）的外显率显著降低。
本研究证实了 NOTCH2 作为 ALGS 的第二个疾病基因的重要性，并扩展了 NOTCH2 相关疾病表型的范围。
