Identification of Novel Mutations in Chinese Infants With Citrullinemia

Zhi Cheng; Xiwen He; Fa Zou; Zhen-E Xu; Chun Li; Hao Liu; Jingkun Miao

doi:10.3389/fgene.2022.783799

Identification of Novel Mutations in Chinese Infants With Citrullinemia

Front Genet. 2022 Mar 3:13:783799. doi: 10.3389/fgene.2022.783799. eCollection 2022.

Authors

Zhi Cheng^{1

2}, Xiwen He², Fa Zou², Zhen-E Xu^{3

4}, Chun Li^{3

4}, Hao Liu⁵, Jingkun Miao⁵

Affiliations

¹ Key Laboratory of Birth Defects and Reproductive Health of the National Health and Family Planning Commission (Chongqing Population and Family Planning Science and Technology Research Institute), Chongqing, China.
² College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
³ Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, China.
⁴ National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
⁵ Neonatal Disease Screening Center, Chongqing Health Center for Women and Children, Chongqing, China.

Abstract

Citrullinemia is a rare autosomal recessive disorder characterized by elevated concentrations of citrulline in the blood resulting from malfunction of the urea cycle. It is categorized into two types, types I and II, which are caused by argininosuccinate synthase 1 (ASS1), and citrin (SLC25A13) gene mutations, respectively. In this study, we performed genetic analysis on nine Chinese infants with citrullinemia using next-generation sequencing, which identified a novel mutation (p.Leu313Met) and a rare mutation (p.Thr323Ile, rs1250895424) of ASS1. We also found a novel splicing mutation of SLC25A13: c.1311 + 4_+7del. Functional analysis of the ASS1 missense mutations showed that both significantly impaired the enzyme activity of ASS1, with the p. Thr323Ile mutation clearly affecting the interaction between ASS1 and protein arginine methyltransferase 7 (PRMT7). These findings expand the mutational spectrum of ASS1 and SLC25A13, and further our understanding of the molecular genetic mechanism of citrullinemia in the Chinese population.

Keywords: ASS1; SLC25A13; citrullinemia; genetic analysis; mutation.