Tags

Type your tag names separated by a space and hit enter

Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency.
Hum Mol Genet 2000; 9(14):2159-65HM

Abstract

Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal recessive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succinyladenosine (S-Ado), the dephosphorylated derivatives of the two substrates of the enzyme. Because ADSL-deficient patients display widely variable degrees of psychomotor retardation, we have expressed eight mutated ADSL enzymes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients. Three expressed mutated ADSL enzymes (M26L, R426H and T450S) were thermolabile, four (A2V, R141W, R303C and S395R) were thermostable and one (del206-218), was inactive. Thermolabile mutations decreased activities with SAICA ribotide (SAICAR) and adenylosuccinate (S-AMP) in parallel, or more with SAICAR than with S-AMP. Patients homozygous for one of these mutations, R426H, displayed similarly decreased ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of approximately 1 in their cerebrospinal fluid and were profoundly retarded. With the exception of A2V, thermostable mutations decreased activity with S-AMP to a much more marked extent than with SAICAR. Two unrelated patients homozygous for one of the thermostable mutations, R303C, also displayed a much more marked decrease in the activity of fibroblast ADSL with S-AMP than with SAICAR, had S-Ado:SAICA riboside ratios between 3 and 4 in their cerebrospinal fluid and were mildly retarded. These results suggest that, in some cases, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio and the patients' mental status.

Authors+Show Affiliations

Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology, Brussels, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10958654

Citation

Race, V, et al. "Clinical, Biochemical and Molecular Genetic Correlations in Adenylosuccinate Lyase Deficiency." Human Molecular Genetics, vol. 9, no. 14, 2000, pp. 2159-65.
Race V, Marie S, Vincent MF, et al. Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency. Hum Mol Genet. 2000;9(14):2159-65.
Race, V., Marie, S., Vincent, M. F., & Van den Berghe, G. (2000). Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency. Human Molecular Genetics, 9(14), pp. 2159-65.
Race V, et al. Clinical, Biochemical and Molecular Genetic Correlations in Adenylosuccinate Lyase Deficiency. Hum Mol Genet. 2000 Sep 1;9(14):2159-65. PubMed PMID: 10958654.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency. AU - Race,V, AU - Marie,S, AU - Vincent,M F, AU - Van den Berghe,G, PY - 2000/8/25/pubmed PY - 2001/2/28/medline PY - 2000/8/25/entrez SP - 2159 EP - 65 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 9 IS - 14 N2 - Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal recessive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succinyladenosine (S-Ado), the dephosphorylated derivatives of the two substrates of the enzyme. Because ADSL-deficient patients display widely variable degrees of psychomotor retardation, we have expressed eight mutated ADSL enzymes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients. Three expressed mutated ADSL enzymes (M26L, R426H and T450S) were thermolabile, four (A2V, R141W, R303C and S395R) were thermostable and one (del206-218), was inactive. Thermolabile mutations decreased activities with SAICA ribotide (SAICAR) and adenylosuccinate (S-AMP) in parallel, or more with SAICAR than with S-AMP. Patients homozygous for one of these mutations, R426H, displayed similarly decreased ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of approximately 1 in their cerebrospinal fluid and were profoundly retarded. With the exception of A2V, thermostable mutations decreased activity with S-AMP to a much more marked extent than with SAICAR. Two unrelated patients homozygous for one of the thermostable mutations, R303C, also displayed a much more marked decrease in the activity of fibroblast ADSL with S-AMP than with SAICAR, had S-Ado:SAICA riboside ratios between 3 and 4 in their cerebrospinal fluid and were mildly retarded. These results suggest that, in some cases, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio and the patients' mental status. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/10958654/Clinical_biochemical_and_molecular_genetic_correlations_in_adenylosuccinate_lyase_deficiency_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/9.14.2159 DB - PRIME DP - Unbound Medicine ER -