RGD Reference Report - Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia. - Rat Genome Database

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Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia.

Authors: Kobayashi, K  Kakinoki, H  Fukushige, T  Shaheen, N  Terazono, H  Saheki, T 
Citation: Kobayashi K, etal., Hum Genet. 1995 Oct;96(4):454-63.
RGD ID: 1599301
Pubmed: PMID:7557970   (View Abstract at PubMed)

Citrullinemia is an autosomal recessive disorder caused by a genetic deficiency of argininosuccinate synthetase (ASS). So far 20 mutations in ASS mRNA have been identified in human classical citrullinemia, including 14 single base changes causing missense mutations in the coding sequence of the enzyme, 4 mutations associated with an absence of exons 5, 6, 7, or 13 in mRNA, 1 mutation with a deletion of the first 7 bases in exon 16 (which is caused by abnormal splicing), and 1 mutation with an insertion of 37 bases between the exon 15 and 16 regions in mRNA. In order to identify the abnormality in the ASS gene causing the exon 7 and 13 deletion mutations and the 37-base insertion mutation between exons 15 and 16 in mRNA, and to establish a DNA diagnostic test, we isolated and sequenced the genomic DNA surrounding each exon. The absence of exon 7 or 13 in ASS mRNA resulted from abnormal splicing caused by a single base change in the intron region: IVS-6(-2) (a transition of A to G at the second nucleotide position within the 3' splice cleavage site of intron 6) and IVS-13(+5) (a transition of G to A at the fifth nucleotide position within the 5' splice cleavage site of intron 13), respectively. The IVS-6(-2) mutation resulted in the creation of an MspI restriction site. DNA diagnostic analysis of 33 Japanese alleles with classical citrullinemia showed that 19 alleles had the IVS-6(-2) mutation (over 50% of the mutated alleles in Japanese patients). It was thus confirmed that one mutation is predominant in Japan. This differs from the situation in the USA where there is far greater heterogeneity. The insertion mutation in mRNA on the other hand resulted from abnormal splicing caused by a 13-bp deletion at the splice-junction between exon 15 and intron 15. The deletion had a short direct repeat (CTCAGG) at the breakpoint junction and presumably resulted from slipped mispairing.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
citrullinemia susceptibilityIAGP 1599301 RGD 
citrullinemia susceptibilityISOASS1 (Homo sapiens)1599301; 1599301 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ass1  (argininosuccinate synthase 1)

Genes (Mus musculus)
Ass1  (argininosuccinate synthetase 1)

Genes (Homo sapiens)
ASS1  (argininosuccinate synthase 1)


Additional Information