Identification of a novel homozygous intron 3 splice site (A>T) mutation in the ARG1 gene in cerebral palsy pediatric cases from Odisha, India

• DOI: 10.1007/s11033-022-07499-7
• Publication Date: 2022-05-03T19:18:13Z
• Authors: Chinmay Kumar Behera; Amit Ranjan Rup; Sagnika Samal; Biswadeep Das
• Keywords: 03 medical and health sciences; 0302 clinical medicine; Arginase; Cerebral Palsy; Mutation; Humans; Urea; Child; Introns; 3. Good health

Abstract Background: Arginases are essential for the completion of the last step of the urea cycle. In hyperarginemia, an autosomal recessive disorder of the urea cycle, a regression of development occurs after the first year of life, followed by gradually progressive atonic cerebral palsy, spastic quadriplegia, and mental decline. ARG1 mutations have been reported in hyperarginemia in the Western population because they obliterated or partially damaged arginase activity. Hence, it is important to assess the ARG1 mutations in such cases of cerebral palsy with hyperarginemia in different populations. Methods and Results: Two pediatric patients of two East Indian families presented with a range of manifestations including hypotonia of all limbs, mental retardation, and multiple episodes of seizure. The onset of the disease ranged from 1 to 3 years of age. Hyperammonemia (> 250 micromoles) and serum hyperarginemia (> 350 micromoles) were observed in both patients. Whole-genome sequencing, followed by Sanger sequencing analysis of both patients confirmed the presence of a homozygous 3' splice site variation in intron 3 of the ARG1 gene (chr6: g.131902357A>T) that affects the invariant AG acceptor splice site of exon 4 (c.330-2A>T; ENST00000356962.2). Conclusion: The study reports the presence of a novel ARG1 mutation in two different pediatric cases from Odisha, India associated with hyperarginemia. The pathogenicity of the mutation was robustly supported by the clinical phenotype, complete co-segregation with the disease, and biochemical observations.