Elsevier

Clinical Biochemistry

Volume 46, Issue 3, February 2013, Pages 209-213
Clinical Biochemistry

Mutation spectrum of the ASS1 gene in Korean patients with citrullinemia type I

https://doi.org/10.1016/j.clinbiochem.2012.10.008Get rights and content

Abstract

Objectives

Citrullinemia type I is a rare metabolic disorder and the distribution of mutations in the ASS1 gene varies among ethnic groups. We aimed to determine the molecular characteristics of citrullinemia type I in Korean patients.

Design and methods

Biochemical and clinical findings were investigated and mutations in the ASS1 gene were identified using direct sequencing method in five patients with high citrulline levels. We also reviewed previous genotypes reported for Korean patients with citrullinemia type I.

Results

We identified five mutations in 10 mutant alleles from the five patients. The most common mutation was the Gly324Ser mutation, which was present in 40% of the mutant alleles, followed by the c.421-2A > G mutation (30% of the mutant alleles). The other mutations (c.1128-6_1188dup67, Arg127Gln, and Arg279Gln) were identified in one mutant allele each. A comprehensive review of previous Korean reports revealed that Gly324Ser, c.421-2A > G, and c.1128-6_1188dup67 mutations accounted for 80.8% of the total mutations reported to date. In terms of genotype–phenotype correlations, a patient homozygous for the c.421-2A > G mutation had fatal clinical manifestations and two patients who were compound heterozygous for the Gly324Ser and c.1128-6_1188dup67 mutations presented with a mild clinical course.

Conclusion

We provided important information about the mutational spectrum of ASS1 gene in Korean patients with citrullinemia type I and demonstrated a difference in common mutations in the ASS1 gene according to ethnic and geographic backgrounds.

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)

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    Citation 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.

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