Li Liting, Dong Jibin, Wang Xiaohong, Guo Hongmei, Wang Huijun, Zhao Jing, Qiu Yiling, Abuduxikuer Kuerbanjiang, Wang Jianshe
Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
School of Pharmacy, Fudan University, Shanghai, China.
PLoS One. 2015 Jun 15;10(6):e0130355. doi: 10.1371/journal.pone.0130355. eCollection 2015.
Alagille syndrome is an autosomal dominant disorder that results from defects in the Notch signaling pathway, which is most frequently due to JAG1 mutations. This study investigated the rate, spectrum, and origin of JAG1 mutations in 91 Chinese children presenting with at least two clinical features of Alagille syndrome (cholestasis, heart murmur, skeletal abnormalities, ocular abnormalities, characteristic facial features, and renal abnormalities). Direct sequencing and/or multiplex-ligation-dependent probe amplification were performed in these patients, and segregation analysis was performed using samples available from the parents. JAG1 disease-causing mutations were detected in 70/91 (76.9%) patients, including 29/70 (41.4%) small deletions, 6/70 (8.6%) small insertions, 16/70 (22.9%) nonsense mutations, 8/70 (11.4%) splice-site mutations, 6/70 (9.4%) missense mutations, and 5/70 (7.1%) gross deletions. Of the mutations detected, 45/62 (72.6%) were novel, and almost all were unique, with the exception of c.439C>T, c.439+1G>A, c.703C>T, c.1382_1383delAC, c.2698C>T, and c.2990C>A, which were detected in two cases each; three cases exhibited entire gene deletions. A majority (69.2%) of the point and frameshift mutations could be detected by the sequencing of eleven exons (exons 3, 5, 6, 11, 14, 16, 18, 21, and 23-25). The mutation detection rate was 50.0% (10/20) in atypical cases that only presented with two or three clinical features of Alagille syndrome. Segregation analysis revealed that 81.1% (30/37) of these mutations were de novo. In conclusion, JAG1 mutations are present in the majority of Chinese pediatric patients with clinical features of Alagille syndrome, and the mutations concentrate on different exons from other reports. Genetic study is important for the diagnosis of atypical Alagille syndrome in Chinese patients.
阿拉吉列综合征是一种常染色体显性疾病，由Notch信号通路缺陷引起，最常见的原因是JAG1基因突变。本研究调查了91名具有至少两种阿拉吉列综合征临床特征（胆汁淤积、心脏杂音、骨骼异常、眼部异常、特征性面部特征和肾脏异常）的中国儿童中JAG1基因突变的发生率、谱系和起源。对这些患者进行了直接测序和/或多重连接依赖探针扩增，并利用从父母处获得的样本进行了分离分析。在70/91（76.9%）的患者中检测到JAG1致病突变，其中包括29/70（41.4%）小缺失、6/70（8.6%）小插入、16/70（22.9%）无义突变、8/70（11.4%）剪接位点突变、6/70（9.4%）错义突变和5/70（7.1%）大片段缺失。在检测到的突变中，45/62（72.6%）是新的，几乎所有都是独特的，但c.439C>T、c.439+1G>A、c.703C>T、c.1382_1383delAC、c.2698C>T和c.2990C>A除外，这几个突变各在两例中检测到；三例表现为整个基因缺失。大部分（69.2%）的点突变和移码突变可通过对11个外显子（外显子3、5、6、11、14、16、18、21以及23至25）进行测序检测到。在仅表现出阿拉吉列综合征两到三种临床特征的非典型病例中，突变检出率为50.0%（10/20）。分离分析显示，这些突变中有81.1%（30/37）是新发的。总之，JAG1突变存在于大多数具有阿拉吉列综合征临床特征的中国儿科患者中，且这些突变集中在与其他报告不同的外显子上。基因研究对中国患者非典型阿拉吉列综合征的诊断很重要。
