Hu Qingyang, Chen Haiming, Liu Tianyi, Dong Xue, Hu Xuejiao, Yan Wenxin, Li Zhong
Department of Pharmacy, Dalian Women and Children's Medical Group, Dalian, Liaoning, China.
College of Pharmacy, Dalian Medical University, Dalian, Liaoning, China.
Front Pediatr. 2024 Sep 12;12:1450859. doi: 10.3389/fped.2024.1450859. eCollection 2024.
Ornithine transcarbamylase deficiency (OTCD), a rare hereditary disease caused by gene mutation of ornithine transcarbamylase (), is the most prevalent type among urea cycle disorders. OTCD typically leads to mitochondrial enzyme dysfunction, preventing the synthesis of citrulline from carbamoyl phosphate and ornithine, and is characterized by a remarkable increase in blood ammonia. Specific symptoms may include neurological abnormalities, growth retardation, and other manifestations.
We presented a case of a child diagnosed with OTCD (OMIM: 311250). By using whole-genome sequencing (WGS) for the pedigree and in-depth whole-exome sequencing (WES), we aimed to identify the disease-causing genes. Gene mutation prediction tools were employed to verify the pathogenicity, and the molecular dynamics simulation method was utilized to assess the impact of this mutation on the activity and structural stability of the protein.
Whole-exome sequencing detected an variant [NM_000531: c.622 (exon6) G > A, p.A208T]. Through comprehensive analysis with various gene mutation prediction tools and in line with the ACMG guidelines, this mutation site was firmly established as a pathogenic site. Moreover, the molecular dynamics simulation results clearly demonstrated that this mutation would significantly compromise the stability of the protein structure.
This study deepens our understanding of the clinical manifestations and characteristics of OTCD, especially the A208T gene mutation site. Given the lack of specific clinical manifestations in OTCD patients, early and accurate diagnosis is crucial for effective treatment and prognosis improvement. To our knowledge, this is the first case of this mutation site reported in China.
鸟氨酸转氨甲酰酶缺乏症（OTCD）是一种由鸟氨酸转氨甲酰酶基因突变引起的罕见遗传性疾病，是尿素循环障碍中最常见的类型。OTCD通常导致线粒体酶功能障碍，阻止氨甲酰磷酸和鸟氨酸合成瓜氨酸，其特征是血氨显著升高。具体症状可能包括神经异常、生长发育迟缓及其他表现。
我们报告了一例被诊断为OTCD（OMIM：311250）的儿童病例。通过对该家系进行全基因组测序（WGS）及深入的全外显子组测序（WES），旨在鉴定致病基因。采用基因突变预测工具验证致病性，并利用分子动力学模拟方法评估该突变对鸟氨酸转氨甲酰酶蛋白活性和结构稳定性的影响。
全外显子组测序检测到一个变异[NM_000531：c.622（外显子6）G＞A，p.A208T]。通过与各种基因突变预测工具进行综合分析，并符合ACMG指南，该突变位点被明确确定为致病位点。此外，分子动力学模拟结果清楚地表明，该突变将显著损害鸟氨酸转氨甲酰酶蛋白结构的稳定性。
本研究加深了我们对OTCD临床表现和特征的理解，尤其是A208T基因突变位点。鉴于OTCD患者缺乏特异性临床表现，早期准确诊断对于有效治疗和改善预后至关重要。据我们所知，这是中国首次报道该突变位点的病例。
