Molecular basis of phenotypic variation in patients with argininemia

Abstract

Argininemia is an autosomal recessive disorder caused by a deficiency in the liver-type arginase enzyme. Clinical manifestations include progressive spastic diplegia and mental retardation. While the quality of life can severely deteriorate in most such patients, some do show remarkable improvement in neurological symptoms while on controlled diets. We examined the thesis that differences in clinical responses to dietary treatment are based on molecular heterogeneity in mutant arginase alleles. Genomic DNAs from 11 patients with argininemia were examined using the polymerase chain reaction, cloning, and sequencing. Nine mutations representing 21/22 mutant alleles were identified in 11 patients with argininemia, and four of these mutations were expressed in vitro to determine the severity of enzymatic defects. We found that these mutations accounted for 64% of the mutant alleles in our patients. Based on findings in vitro expression tests, the mutations can be considered either severe or moderate. Patients with at least one moderate mutant allele responded well to dietary treatment; concentrations of plasma arginine were controlled within 300 microM. In contrast, patients with two severely mutated alleles did not respond to dietary treatment and plasma arginine was over 400 microM. Argininemia is heterogeneous at the molecular level. The degree of clinical improvement during dietary treatment is reflected in the concentration of arginine in plasma, as a measure of metabolic control. Plasma arginine levels during treatment is reflected in the concentration of arginine in plasma, as a measure of metabolic control. Plasma arginine levels during treatment correlated with types of molecular defects in the arginase genes.

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

“…Nonsense mutations have been reported in a minority of patients, with missense mutations being more prevalent [Uchino et al, 1995;Vockley et al, 1994]. Many of these missense mutations occur in highly conserved regions of the gene .…”

Subunit-Subunit Interactions in Trimeric Arginase

“…Hyperargininemia is a heterogeneous disease resulting from point mutations throughout the type I arginase gene (11)(12)(13)(14)(15)(16)(17). An R291X mutation has been identified that would lead to the production of a truncated protein lacking the final 32 amino acids at the C terminus of the 323 amino acid subunit.…”

Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia

“…At least 12 distinct disease-causing mutations in ARG1 have been identified so far in different human populations, indicating that argininemia is heterogeneous at the molecular level (Haraguchi et al, 1990;Grody et al 1992;Uchino et al 1992, Vockley et al, 1994Uchino et al, 1995). In this work we extend the sequence data on arginase deficiency by characterizing a novel R21X mutation found in four homozygous Portuguese patients with argininemia.…”

“…Based on the results from in vitro expression tests, Uchino et al (1995) proposed that ARG1 pathogenic mutations could be classified as either severe or moderate and further suggested that the clinical responses to dietary treatment were correlated with the nature of these mutations. Among the severe mutations, Uchino et al (1995) included the deletion 77delA, which leads to a shift in the reading frame after aminoacid residue 26 and creates a premature termination at codon 31.…”

“…Among the severe mutations, Uchino et al (1995) included the deletion 77delA, which leads to a shift in the reading frame after aminoacid residue 26 and creates a premature termination at codon 31. Since the mutation now described leads to termination at codon 21, its pathogenic nature seems obvious.…”