RGD Reference Report - Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. - Rat Genome Database

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Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.

Authors: Walker, DC  McCloskey, DA  Simard, LR  McInnes, RR 
Citation: Walker DC, etal., Proc Natl Acad Sci U S A 1990 Dec;87(24):9625-9.
RGD ID: 734610
Pubmed: PMID:2263616   (View Abstract at PubMed)
PMCID: PMC55225   (View Article at PubMed Central)

Argininosuccinic acid lyase (ASAL) deficiency is a clinically heterogeneous autosomal recessive urea cycle disorder. We previously established by complementation analysis that 28 ASAL-deficient patients have heterogeneous mutations in a single gene. To prove that the ASAL structural gene is the affected locus, we sequenced polymerase chain reaction-amplified ASAL cDNA of a representative mutant from the single complementation group. Fibroblast strain 944 (approximately 1% of residual ASAL activity), from a late-onset patient who was the product of a consanguineous mating, had only a single base-pair change in the coding region, a C-283----T transition at a CpG dinucleotide in exon 3. This substitution converts Arg-95 to Cys (R95C), occurs in a stretch of 13 residues that is identical in yeast and human ASAL, and was present in both of the patient's alleles but not in 14 other mutant or 10 normal alleles. Expression in COS cells demonstrated that the R95C mutation produces normal amounts of ASAL mRNA but little protein and less than 1% ASAL activity. We observed that amplified cDNA from mutant 944 and normal cells (liver, keratinocytes, lymphoblasts, and fibroblasts) contained, in addition to the expected 5' 513-base-pair band, a prominent 318-base-pair ASAL band formed by the splicing of exon 2 from the transcript. The short transcript maintains the ASAL reading frame but removes Lys-51, a residue that may be essential for catalysis, since it binds the argininosuccinate substrate. We conclude (i) that the identification of the R95C mutation in strain 944 demonstrates that virtually all ASAL deficiency results from defects in the ASAL structural gene and (ii) that minor alternative splicing of the coding region occurs at the ASAL locus.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
amino acid metabolic disorder  IAGP 734610Argininosuccinic Aciduria and DNA:mutations:multiple (human)RGD 
amino acid metabolic disorder  ISOASL (Homo sapiens)734610; 734610Argininosuccinic Aciduria and DNA:mutations:multiple (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Asl  (argininosuccinate lyase)

Genes (Mus musculus)
Asl  (argininosuccinate lyase)

Genes (Homo sapiens)
ASL  (argininosuccinate lyase)


Additional Information