Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients
Abstract
Adenylosuccinate lyase (ADSL) is a bifunctional enzyme acting in de novo purine synthesis and purine nucleotide recycling. ADSL deficiency is a selectively neuronopathic disorder with psychomotor retardation and epilepsy as leading traits. Both dephosphorylated enzyme substrates, succinylaminoimidazole-carboxamide riboside (SAICAr) and succinyladenosine (S-Ado), accumulate in the cerebrospinal fluid (CSF) of affected individuals with S-Ado/SAICAr concentration ratios proportional to the phenotype severity. We studied the disorder at various levels in a group of six patients with ADSL deficiency. We identified the complete ADSL cDNA and its alternatively spliced isoform resulting from exon 12 skipping. Both mRNA isoforms were expressed in all the tissues studied with the non-spliced form 10-fold more abundant. Both cDNAs were expressed in Escherichia coli and functionally characterized at the protein level. The results showed only the unspliced ADSL to be active. The gene consists of 13 exons spanning 23 kb. The promotor region shows typical features of the housekeeping gene. Eight mutations were identified in a group of six patients. The expression studies of the mutant proteins carried out in an attempt to study genotype-phenotype correlation showed that the level of residual enzyme activity correlates with the severity of the clinical phenotype. All the mutant enzymes studied in vitro displayed a proportional decrease in activity against both of their substrates. However, this was not concordant with strikingly different concentration ratios in the CSF of individual patients. This suggests either different in vivo enzyme activities against each of the substrates and/or their different turnover across the CSF-blood barrier, which may be decisive in determining disease severity.
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Different amino acid changes around the site of an AMH-specific derived protein, ADSL (A429V), can bring about adenylosuccinate lyase deficiency (R426H; D430N), the symptoms of which include developmental delay, autistic-like traits, aggressiveness, and microcephaly.
“Different amino acid changes around the site of an AMH-specific derived protein, ADSL (A429V), can bring about adenylosuccinate lyase deficiency (R426H; D430N [118]), the symptoms of which include developmental delay, autistic-like traits, aggressiveness, and microcephaly [119].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [118]
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- Authors
- Kmoch, S.
- Affiliations
- Charles University (CZ)
- Corresponding author
- Kmoch, S.
- ORCID
- Kmoch, S.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-06-12
- Volume
- 9
- Issue
- 10
- Pages
- 1501-1513
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2168615373
- Cited by
- 90
- References
- 35
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 6 · 2012: 2
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Grantová Agentura České Republiky
- Ministerstvo Zdravotnictví Ceské Republiky
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- adenylosuccinate lyase deficiency, adenylosuccinate lyase, cDNA cloning, alternative splicing, purine metabolism, SAICAR, cerebrospinal fluid, genotype-phenotype correlation, residual enzyme activity, disease severity, epilepsy, psychomotor retardation
- MeSH terms
- Adenylosuccinate Lyase, Amino Acid Sequence, Base Sequence, Cells, Cultured, Child, Child, Preschool, Cloning, Molecular, Escherichia coli, Exons, Female, Fibroblasts, Genotype, Humans, Infant, Kinetics, Male, Molecular Sequence Data, Mutation, Phenotype, Promoter Regions, Genetic, Temperature, Tissue Distribution, Alternative Splicing, Sequence Analysis, DNA, DNA, Complementary, Protein Isoforms
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