Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene

Abstract

Citrullinemia type I is an autosomal recessive disorder that is caused by a deficiency of the urea cycle enzyme argininosuccinate synthetase (ASS1). Deficiency of ASS1 shows various clinical manifestations encompassing severely affected patients with fatal neonatal hyperammonemia as well as asymptomatic individuals with only a biochemical phenotype. This is a comprehensive report of all 87 mutations found to date in the ASS1 gene on chromosome 9q34.1. A large proportion of the mutations (n 5 27) are described here for the first time. Mutations are distributed throughout exons 3 to 15, most of them being identified in exons 5, 12, 13, and 14. The mutation G390R in exon 15 is the single most common mutation in patients with the classical phenotype. Certain mutations clearly link to specific clinical courses but the clinical phenotype cannot be anticipated in all patients. This update presents a survey of the correlation between mutations in the ASS1 gene and the respective clinical courses as described so far. It also sheds light on the geographic incidence of the mutations. Enzymatic studies have been done in bacterial and human cell systems. However, the prognostic value of genetic aberrations with respect to their effect on protein function and clinical manifestation remains uncertain.

Mutation analysis of Indian patients with urea cycle defects

“…Other two mutations R157H and R265C respectively have also been described in patients with severe phenotype [2]. However, in our case R265C mutation was observed in patient with milder phenotype suggesting that the genotype phenotype correlation may not be very strong.…”

“…The mutation G390R in exon 15 is the single most common mutation in patients with the classical phenotype [2]. Mild, or late-onset citrullinemia type I was found to be associated with a number of specific mutations [2]. Two of our early onset patients had R157H (case 2) G390R (case 3) mutation respectively whereas the patient with milder form had R265C mutation.…”

“…Till date, 87 mutations have been found, distributed throughout exons 3 to 15, most of them being identified in exons 5,12,13, and 14 and in several intervening sequences, leading to abnormal messenger RNA splicing. The mutation G390R in exon 15 is the single most common mutation in patients with the classical phenotype [2]. Mild, or late-onset citrullinemia type I was found to be associated with a number of specific mutations [2].…”

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

“…This mutation has been previously described in at least two patients with autosomal recessive citrullinemia. 15,16 Case 9 is a 24-day-old female baby with wholechromosome UPD16 suspected to have Bardet--Biedl syndrome 2 (OMIM #209900 and 606151, BBS2 gene at 16q12.2). A homozygous frameshift mutation in exon 14 of BBS2 gene was identified and predicted to lead to a premature stop codon (NM_031885.3:c.1770delT, [p.(Phe590Leufs*8]).…”

Molecular Epidemiology of Citrullinemia Type I in a Risk Region of Argentina: A First Step to Preconception Heterozygote Detection

“…Specifically, the substitution p.G390R (c.1168G>A) is one of the most common mutation described in cases of CTLN1 in different ethnic groups. This mutation has been exclusively associated, in homozygous condition, with an early/severe phenotype (Engel et al 2009). …”