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Additional mutations in argininosuccinate synthetase causing citrullinemia
K Kobayashi1, C Rosenbloom, A L Beaudet
1Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.
Molecular Biology & Medicine
|February 1, 1991
Summary
Two new mutations causing citrullinemia, a genetic disorder, were identified. Most missense mutations in citrullinemia patients occur in highly conserved gene regions.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Argininosuccinate synthetase deficiency leads to arginine auxotrophy in lower organisms and citrullinemia in humans and cattle.
- Previous research identified seven missense mutations, four exon-deletion mutations, and one splicing mutation in human neonatal citrullinemia.
Purpose of the Study:
- To identify additional genetic mutations responsible for citrullinemia.
- To analyze the conservation and mutation patterns in argininosuccinate synthetase.
Main Methods:
- Reverse transcription of mRNA, cDNA amplification, and sequencing of cDNA clones were employed.
- Sequence analysis was performed on identified mutations.
Main Results:
- Two novel missense mutations causing citrullinemia were discovered: serine to leucine at position 18 (S18L) and arginine to cysteine at position 86 (R86C).
- Both new mutations, along with eight of nine previously identified missense mutations, involve C-to-T transitions in CpG dinucleotides.
- Six of nine human missense mutations affect amino acid positions conserved across multiple species, including mammals, yeast, and bacteria.
Conclusions:
- Human citrullinemia is caused by highly heterogeneous mutations in the argininosuccinate synthetase gene.
- The identified mutations, particularly those in CpG dinucleotides and conserved regions, provide insights into the molecular basis of citrullinemia.
- All studied non-consanguineous individuals with citrullinemia were compound heterozygotes, indicating complex inheritance patterns.