Potential role of ARG1 c.57G > A variant in Argininemia

Yixiao Li; Rujin Tian; Dong Wang; Haozheng Zhang; Yi Zhou; Chunli Ma; Han Zhang; Kaihui Zhang; Shu Liu

doi:10.1007/s13258-024-01595-7

Potential role of ARG1 c.57G > A variant in Argininemia

Genes Genomics. 2024 Nov 20. doi: 10.1007/s13258-024-01595-7. Online ahead of print.

Authors

Yixiao Li^#^{1

2

3}, Rujin Tian^#¹, Dong Wang¹, Haozheng Zhang¹, Yi Zhou⁴, Chunli Ma⁵, Han Zhang⁶, Kaihui Zhang⁷, Shu Liu⁸

Affiliations

¹ Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, Shandong, China.
² Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250001, Shandong, China.
³ Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
⁴ Department of Ophthalmology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
⁵ Shandong Academy of Medical Science, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
⁶ Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250001, Shandong, China. zhanghan0696@139.com.
⁷ Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, Shandong, China. khz83@163.com.
⁸ Pediatric Endocrinology and Inherited Metabolic Department, Guangdong Women and Children Hospital, Guangzhou, 511442, Guangdong, China. shmicy@163.com.

^# Contributed equally.

PMID: 39567422
DOI: 10.1007/s13258-024-01595-7

Abstract

Background and objective: Argininemia (OMIM: 207800), as well as arginase deficiency, a disorder of the urea cycle caused by deficiency of arginase 1 (ARG1, NP_000036.2), is a scarce autosomal recessive genetic disease. The patients who suffered with argininemia often showed spastic paraplegia, epileptic seizures, severe mental retardation, and even the hyperammonemia. In neonatal screening, we found a healthy baby with mild elevated arginine levels. We have demonstrated the genetic etiology of the patient.

Methods: The patient's clinical characteristic and family history were collected. The technologies including Next Generation Sequencing (NGS), Sanger sequencing, Bioinformatics Analysis, RNA extraction, cDNA obtained, Sanger sequencing, Minigene splicing assay, Real-time PCR, Single-molecule real-time (SMRT) sequencing were applied.

Results: One homozygous variant, c.57G > A (p.Q19=), was identified in the proband, which was inherited from the parents. Through different detection methods, we found that the c.57G > A variant causes three different transcriptional versions: normal mRNA (mRNA from blood), mRNA with the exon2 deletion (73bp, mRNA from blood and minigene assay), and mRNA sequence from the SMRT sequencing (parts of exons and introns were detected, including exon 1-4, intron 1 and 4, and part of intron 2, 3, and 5). The expression of ARG1 mRNA and protein also decreased in the blood. The related genes of NMD (Nonsense-mediated mRNA decay), SMG1, UPF1, and UPF3b, were expressed higher than the controls in the blood, which hints the NMD could play a role in the mRNA decay regarding the cDNA with 73bp deletion by c.57G > A variant.

Conclusions: The study is the first study considering a synonymous variant of the ARG1 gene influencing alternative splicing(AS). Otherwise, the variant c.57G > A is relatively frequent in the general population( MAF = 0.0146). Our discovery revealed the variant possesses partial pathogenic potential, which would contribute to the deeper understanding and gold model for the intricate relationship between genetic mutations, arginine metabolism, and physical function.

Keywords: ARG1; Argininemia; Minigene splicing assay; SMRT sequencing; Synonymous mutation.

Abstract

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