Characterization and mRNA expression analysis of a novel ARG1 splicing mutation causing hyperargininemia

Biallelic mutations in the ARG1 gene result in an uncommon autosomal recessive inborn defect of the urea cycle known as hyperargininemia (OMIM #207800). ARG1 splicing mutations are not reported often, and they are probably related to a more severe phenotype than missense mutations. In this article, we describe the results of molecular studies in a young hyperargininemia patient carrying a novel splicing mutation in ARG1. Molecular analyses included PCR amplification and direct nucleotide sequencing of the ARG1 gene. RT-PCR analysis was performed to investigate the effect of the mutation in mRNA splicing and in the expression of ARG1 isoforms. Mutational analysis identified a novel homozygous ARG1 IVS4-1G>C point mutation in the patient's DNA. Blood leukocyte mRNA was analyzed to demonstrate the splicing defect caused by this mutation. Sequencing of ARG1 RT-PCR products allowed the characterization of a mutated transcript retaining 51-bp from intron 4. In addition, two new, alternatively spliced ARG1 transcripts lacking either exon 4 or exons 4 and 5 were identified in mRNA from the patient and from controls. Our results expand the mutational spectrum in hyperargininemia patients and indicate that the novel splicing mutation results in an aberrant transcript retaining intronic sequences. Two novel alternatively spliced ARG1 transcripts were also recognized. •Hyperargininemia is a rare disorder arising from ARG1 mutations.•ARG1 splicing mutations have been rarely described.•A novel homozygous ARG1 splicing mutation is reported.•RT-PCR analysis demonstrated RNA splicing defects and the identification of two novel ARG1 transcripts.