Mutation spectrum of the ASS1 gene in Korean patients with citrullinemia type I
Graphical abstract
Highlights
► We determined the molecular characteristics of citrullinemia type I in Koreans. ► Biochemical and clinical findings were investigated in each patient. ► We reviewed previous genotype data in Korean patients with citrullinemia type I. ► The comparison of mutation frequency according to ethnicity was performed.
Introduction
Citrullinemia type I (MIM# 215700) is a rare autosomal recessive disorder caused by a deficiency of argininosuccinate synthetase (EC 6.3.4.5), which is a urea cycle enzyme [1]. The incidence of citrullinemia ranges from 1:44,300 to 1:200,000 based on a newborn screening test using tandem mass spectrometry [2], [3].
Classically, disease onset occurs during the early neonatal period with hyperammonemia and neurologic manifestations, and significant neurologic sequelae result, even after immediate treatment [1]. In other patients, symptomatic hyperammonemia develops during adulthood or pregnancy, and a considerable number of patients present with a mild and asymptomatic disease course [1], [4], [5]. To control and prevent hyperammonemia, patients are treated by removing nitrogen, either via medications or by hemodialysis, dietary protein restriction, and prevention of a catabolic status with adequate nutrition [6], [7]. In the classic form of citrullinemia type I, hyperammonemia and citrullinemia (usually > 1,000 μmol/L; normal < 50–60 μmol/L) are typical findings, and elevated plasma glutamine levels, low plasma arginine, and orotic aciduria are also found [1].
Diagnosis of citrullinemia type I relies on biochemical and molecular genetic studies. The ASS1 gene (MIM# 603470) is the only gene in which mutations associated with citrullinemia type I have been found. The human ASS1 gene is located on chromosome 9q34.1 and spans 56 kb. It contains 16 exons encoding 412 amino acids, and about 15 pseudogenes have been reported [8], [9]. Over 87 mutations are known to cause citrullinemia type I [5]. The mutation Gly390Arg on exon 15 is known to be the most common mutation in the classic form [5].
To date, eight Korean patients have been documented to be positive for citrullinemia type I based on molecular genetic studies [10], [11], [12], [13], [14]. In this study, we identified five neonates with citrullinemia type I by molecular analysis of the ASS1 gene. Our goals in this study were to investigate the molecular, biochemical, and clinical characteristics of citrullinemia type I, and to expand the global pool of citrullinemia type I reports.
Section snippets
Patients
Whole blood samples from five patients with elevated citrulline levels were referred to the Department of Laboratory Medicine and Genetics at Samsung Medical Center between April 2004 and April 2012. Clinical and biochemical data were collected. The study was approved by the Institutional Ethics Committee of Samsung Medical Center. In addition, we reviewed previous literature on patients from Korean with citrullinemia type I.
Direct sequencing analysis of the ASS1 gene
Genomic DNA was extracted from peripheral blood leukocytes of each
Clinical and biochemical characteristics of patients with citrullinemia type I
We identified five Korean patients with citrullinemia type I. All patients had high citrulline levels (> 1,000 μmol/L) and no significant problems at birth. The clinical and biochemical characteristics of these patients are summarized in Table 2.
Patient 1 was born at a gestational age of 39 weeks and 4 days by cesarean section, and her weight at birth was 3,600 g. She was the first baby of a healthy mother and had no clinical manifestations of metabolic disorder at the time of birth. However, at 8
Discussion
Mutations in the ASS1 gene that cause citrullinemia type I have been sporadically identified in Korean. In this study, we aimed to determine the molecular spectrum and phenotypic characteristics of citrullinemia type I in Korean patients by identifying mutations in the ASS1 gene and correlating the genotypes with clinical and biochemical manifestations.
In present study, molecular genetic analysis of the ASS1 gene identified 10 mutant alleles in five patients. During the study period, mutations
Conflict of interest
The authors certify that there are no conflicts of interest with any financial organizations regarding the material discussed in the article. No writing assistance was utilized in the production of this article.
Acknowledgments
This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A120030).
References (20)
- et al.
Mild citrullinemia in caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1)
Mol Genet Metab
(2003) - et al.
Nutritional management of urea cycle disorders
Crit Care Clin
(2005) - et al.
Mutation analysis of korean patients with citrullinemia
Mol Cells
(2000) - et al.
Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia
Hum Genet
(1995) - et al.
30-year follow-up of a patient with classic citrullinemia
Mol Genet Metab
(2012) - et al.
Tandem mass spectrometric analysis for disorders in amino, organic and fatty acid metabolism: two year experience in South Korea
Southeast Asian J Trop Med Public Health
(2003) Expanded newborn screening by tandem mass spectrometry: the massachusetts and new england experience
Southeast Asian J Trop Med Public Health
(2003)- et al.
Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype–phenotype correlation in 38 classical citrullinemia patients
Hum Mutat
(2003) - et al.
Mutations and polymorphisms in the human argininosuccinate synthetase (ass1) gene
Hum Mutat
(2009) Long-term outcome of patients with urea cycle disorders and the question of neonatal screening
Eur J Pediatr
(2003)
Cited by (10)
Urea cycle disorders
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1Molecular genetics of citrullinemia types I and II
2014, Clinica Chimica ActaCitation Excerpt :The mutation detection rate is quite high, being greater than 90% in various ethnic groups, indicating that mutations are clustered in the exons and exon–intron boundaries of the ASS1 gene [12,45]. The Gly390Arg mutation is the most common mutation in multiple ethnic groups, including Germans, Spaniards, and Turks but not in Asians [12,46,47], whereas c.421-2A > G is the most common mutation in East Asians (up to 60% in Japanese) [45,48,49]. Although the distribution and spectrum of mutations are various according to ethnic background, mutations with high frequency have been identified in some ethnicities, including Japanese, Korean, and Turkish ethnic groups.
Citrullinemia type I in Chinese children: Identification of two novel argininosuccinate synthetase gene mutations
2022, Frontiers in PediatricsMaternal death after postpartum onset of citrullinemia type Ⅰ: a case report
2021, Chinese Journal of Perinatal Medicine