Functional identification of two novel variants and a hypomorphic variant in ASS1 from patients with Citrullinemia type I.
Functional identification of two novel variants and a hypomorphic variant in ASS1 from patients with Citrullinemia type I.
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DOI：
10.3389/fgene.2023.1172947
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发表时间：
2023
影响因子：
3.7
通讯作者：
Wu, Lingqian
中科院分区：
文献类型：
--
作者：
Liu, Jing;Wang, Zhongjie;Yan, Huiming;Teng, Yanling;Shi, Qingxin;Chen, Jing;Tang, Wanglan;Yu, Wenxian;Peng, Ying;Xi, Hui;Ma, Na;Liang, Desheng;Li, Zhuo;Wu, Lingqian
背景资料：瓜氨酸血症I型（CTLN 1）是一种罕见的常染色体隐性遗传性尿素循环缺陷，由编码琥珀酸合成酶（ASS 1）的基因突变引起。典型的CTLN 1通常表现为急性高氨血症和神经系统症状。分子遗传学检测对患者诊断至关重要。 方法：收集3个临床疑似CTLN 1家系，均为非血缘关系。使用全外显子组测序（WES）鉴定潜在的致病性变体，并使用桑格测序进行验证。Western印迹、定量PCR、免疫荧光染色和ELISA用于评估候选ASS 1变体的功能变化。 结果：共鉴定出5个变异株，其中2个为新发现，1个已报道，但致病性尚未验证。新的变体c.649- 651 del（p.P217del）和5′UTR变体（c.-P217 del）被克隆到p217 del基因中。4C>T）导致ASS 1在蛋白和转录水平上的表达降低。另一个新的变体c.1048C>T（p.Q350*）在蛋白质水平上表现出明显的表达下降，形成截短的蛋白质，但转录增加。c.649_651del（p.P217del）和c.1048C>T（p.Q350*）都显示出酶活性的高度显著降低，而c.-651 del（p.P217del）和c.1048C>T（p.Q350*）都显示出酶活性的高度显著降低。4C>T没有影响。 结论：我们在ASS 1中发现了两个新的变异体和一个亚态非编码变异体，并通过功能研究验证了其致病性。我们的研究结果有助于扩大ASS 1变体的谱，并了解CTLN 1的基因型-表型关系。
Background: Citrullinemia type I (CTLN1) is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the gene encoding the arginosuccinate synthetase (ASS1) enzyme. Classic CTLN1 often manifests with acute hyperammonemia and neurological symptoms. Molecular genetic testing is critical for patient diagnosis. Methods: Three unrelated families with clinically suspected CTLN1 were included in this study. Potential pathogenic variants were identified using whole exome sequencing (WES) and validated using Sanger sequencing. Western blotting, quantitative PCR, immunofluorescent staining, and ELISA were used to assess functional changes in candidate ASS1 variants. Results: Five variants were identified, two of which were novel, and one has been reported, but its pathogenicity was not validated. The novel variant c.649-651del (p.P217del) and the 5′UTR variant (c.-4C>T) resulted in a decrease in ASS1 expression at both the protein and transcription levels. The other novel variant, c.1048C>T (p.Q350*), showed a marked decrease in expression at the protein level, with the formation of truncated proteins but an increased transcription. Both c.649_651del (p.P217del) and c.1048C>T (p.Q350*) showed a highly significant reduction in enzyme activity, while c.-4C>T had no effect. Conclusion: We identified two novel variants and a hypomorphic non-coding variant in ASS1 and validated the pathogenicity using functional studies. Our findings contribute to expanding the spectrum of ASS1 variants and understanding the genotype-phenotype relationships of CTLN1.
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影响因子：
5.6
作者：
Li, Menglin;Li, Zhuo;Chen, Miaomiao;Hu, Zhiqing;Zhou, Miaojin;Wu, Lingqian;Zhang, Chunhua;Liang, Desheng
通讯作者：
Liang, Desheng
影响因子：
3.9
作者：
Engel, Katharina;Hoehne, Wolfgang;Haeberle, Johannes
通讯作者：
Haeberle, Johannes
DOI：
10.3760/cma.j.issn.1003-9406.2011.06.007
发表时间：
2011-12-01
期刊：
Zhonghua Yixue Yichuanxue Zazhi
影响因子：
--
作者：
Hu Ping;Zhou Xiao-yan;Xu Zheng-feng
通讯作者：
Xu Zheng-feng
影响因子：
13.3
作者：
Li, S.;Li, H.;Wu, L.
通讯作者：
Wu, L.
影响因子：
3.8
作者：
Miller, Marcus J.;Soler-Alfonso, Claudia R.;Sutton, V. Reid
通讯作者：
Sutton, V. Reid