NOTCH2 mutations in Alagille syndrome.
NOTCH2 mutations in Alagille syndrome.
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DOI：
10.1136/jmedgenet-2011-100544
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发表时间：
2012-02
影响因子：
4
通讯作者：
Spinner NB
中科院分区：
文献类型：
--
作者：
Kamath BM;Bauer RC;Loomes KM;Chao G;Gerfen J;Hutchinson A;Hardikar W;Hirschfield G;Jara P;Krantz ID;Lapunzina P;Leonard L;Ling S;Ng VL;Hoang PL;Piccoli DA;Spinner NB
Alagille综合征（ALGS）是一种显性的多系统疾病，94%的患者由Jagged1（JAG 1）配体突变引起，<1%的患者由NOTCH 2受体突变引起。迄今为止，只有两个NOTCH 2家族被报道。这项研究假设，额外的NOTCH 2突变将存在于没有JAG 1突变的ALGS临床特征的患者中。该研究筛选了一组具有提示或诊断ALGS的NOTCH2突变的临床特征的JAG1阴性个体。鉴定出8个具有新型NOTCH2突变的个体（6个错义突变、1个剪接突变和1个无义突变）。其中3例患者符合ALGS的经典标准，5例患者仅具有一个子集的特征。突变分布在蛋白质的胞外（N=5）和胞内结构域（N=3）。四个错义，一个无义，和一个剪接突变的功能分析表明，这些蛋白质的Notch信号减少。与JAG1个体一样，NOTCH2突变的受试者表现出受影响系统的高度可变表达性。肝脏受累在NOTCH 2先证者中是普遍的，他们与JAG 1患者的眼科和肾脏异常患病率相似。在NOTCH 2组中有心脏受累较少的趋势（60% vs JAG 1中的100%）。与JAG 1（+）队列相比，NOTCH 2（+）先证者的脊椎异常率（10%）和面部特征（20%）显著降低。这项工作证实了NOTCH2作为ALGS中第二个疾病基因的重要性，并扩展了NOTCH2相关疾病表型的库。
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.
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影响因子：
3.9
作者：
Majewski, Jacek;Schwartzentruber, Jeremy A.;Samuels, Mark E.
通讯作者：
Samuels, Mark E.
影响因子：
30.8
作者：
Li, LH;Krantz, ID;Spinner, NB
通讯作者：
Spinner, NB
影响因子：
3
作者：
Bérard, E;Sarles, J;Niaudet, P
通讯作者：
Niaudet, P
影响因子：
13.5
作者：
Emerick, KM;Rand, EB;Piccoli, DA
通讯作者：
Piccoli, DA
影响因子：
3.3
作者：
Shannon, Edward;Noveck, Robert;Kamath, Burde
通讯作者：
Kamath, Burde