Identification of mutations in Malaysian patients with argininosuccinate lyase (ASL) deficiency

Ernie Zuraida Ali; Yusnita Yakob; Lock Hock Ngu

doi:10.1016/j.ymgmr.2019.100525

Identification of mutations in Malaysian patients with argininosuccinate lyase (ASL) deficiency

Mol Genet Metab Rep. 2019 Oct 24:21:100525. doi: 10.1016/j.ymgmr.2019.100525. eCollection 2019 Dec.

Authors

Ernie Zuraida Ali¹, Yusnita Yakob², Lock Hock Ngu³

Affiliations

¹ Inborn Error of Metabolism and Genetic Unit, Nutrition, Metabolism and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Section U13 Setia Alam, 40170 Shah Alam, Selangor, Malaysia.
² Molecular Diagnostics and Protein Unit, Specialized Diagnostics Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.
³ Medical Genetics Department, Kuala Lumpur Hospital, Ministry of Health Malaysia, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.

Abstract

Argininosuccinate lyase (ASL) deficiency impairs the function of the urea cycle that detoxifies blood ammonia in the body. Mutation that occurs in the ASL gene is the cause of occurrence of ASL deficiency (ASLD). This deficiency causes hyperammonemia, hepatopathy and neurodevelopmental delay in patients. In this study, the clinical characteristics and molecular analysis of 10 ASLD patients were presented. 8 patients were associated with severe neonatal onset, while the other 2 were associated with late onset. Molecular analysis of ASL gene identified four new missense variants, which were c.778C>T, p.(Leu260Arg), c.1340G>C, p.(Ser447Thr), c.436C>G, p.(Arg146Gly) and c.595C>G, p.(Leu199Val) and four reported missense variants, which were c.638G>A, p.(Arg213Gln); c.556C>T, p.(Arg186Trp), c.578G>A, p.(Arg193Gln) and c.436C>G, p.(Arg146Trp). In silico servers predicted all new and reported variants as disease-causing. Structural examination exhibited that all pathogenic variants affected the stability of the tetrameric ASL structure by disturbing the bonding pattern with the neighboring residues.

Conclusion: This study revealed the genetic heterogeneity among Malaysian ASL patients. This study has also expanded the mutational spectrum of the ASL.

Keywords: ASLD; Argininosucinate lyase deficiency; Autosomal recessive; Hyperammonemia; Mutation.