Molecular basis of argininemia. Identification of two discrete frame-shift deletions in the liver-type arginase gene.

Abstract

Argininemia results from a deficiency of arginase (EC 3.5.3.1), the last enzyme of the urea cycle in the liver. We examined the molecular basis for argininemia by constructing a genomic library followed by cloning and DNA sequencing. Discrete mutations were found on two alleles from the patient, a product of a nonconsanguineous marriage. There was a four-base deletion at protein-coding region 262-265 or 263-266 in exon 3 that would lead to a reading-frame shift after amino acid residue 87 and make a new stop codon at residue 132. The other was a one-base deletion at 77 or 78 in exon 2 that would lead to a reading-frame shift after residue 26 and make a stop codon at residue 31. For confirmation, genomic DNAs from the patient and from her parents were amplified by the polymerase chain reaction method. The patient was shown to be a compound heterozygote, inheriting an allele with the four-base deletion from the father and the other allele with the one-base deletion from the mother. These data seem to be the first evidence of a case of argininemia caused by two different deletion mutations. (J. CliU. Invest. 1990. 86:347-350.)

Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia

“…The mutations reported in this paper as well as the mutations previously reported by us (Grody et al, 1992), Uchino et al (1992) and by Haraguchi et al (1990) indicate that arginase deficiency is genetically heterogeneous at the molecular level.…”

“…The deletion mutations which introduce premature chain terminations, identified by Haraguchi et al (1990) and Uchino et al (1992), confirm these observations. The lack of conservative mutations which do not affect protein function in our patient population indicates that arginase may be tolerant of such mutations and only mutations which drastically reduce arginase activity, such as premature stops and mutations within the active site, result in the disease state.…”

“…Mutations have been reported previously by Uchino et al (1992) and Haraguchi et al (1990) in the arginase genes of several Japanese patients. These mutations have been confirmed to reduce arginase activity by in vitro expression studies.…”

Mucopolysaccharidosis type IVA. N-acetylgalactosamine-6-sulfate sulfatase exonic point mutations in classical Morquio and mild cases.

“…At The two-base deletion observed in classical Morquio disease (1 342delCA) was located in a short tandem repeat sequence of TCACAACTCACAA (nucleotides 1335-1347). Since repeat sequences are often involved in DNA rearrangements (22)(23)(24), the 1342delCA deletion appears to be the result of slipped mispairing. The resulting product drastically altered the polypeptide structure, as a result of frame shift, thereby suggesting that the 1342delCA deletion led to a truncated, unstable and, rapidly degraded polypeptide with no detectable enzyme activity, hence, the severe form of the disease.…”

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations

“…The ARG1 gene spans 11.1 kb, maps to 6q23, has an open reading frame of 1,393 bp and harbors eight exons. The ∼50 disease‐associated mutations reported so far (Amayreh, Meyer, & Das, ; Cardoso, Martins, Vasconcelos, Vilarinho, & Rocha, ; Carvalho et al., ; Cohen et al., ; Edwards et al., ; Haraguchi et al., ; Hertecant, Al‐Gazali, Karuvantevida, & Ali, ; Häberle & Koch, ; Jain‐Ghai, Nagamani, Blaser, Siriwardena, & Feigenbaum, ; Korman et al., ; Kuster, Benoist, Caillaux, Muller, & Acquaviva, ; Lee, Jin, Kim, Choi, & Yoo, ; Mullane, Errico, & Evans, ; Mustafa et al., ; Schiff et al., ; Scholl‐Bürgi et al., ; Segawa et al., ; Tsang et al., ; Uchino et al., ; Uchino et al., ; Vockley et al., ,b; Vockley et al., ; Wu et al., ; Wu et al., ) spread out across the eight exons and at some exon–intron boundary splice sites. In this article, we compile all published mutations and all mutations recently identified in our laboratory.…”