Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency

• Published in: Human molecular genetics 2000-09, Vol.9 (14), p.2159-2165
• Main Authors: RACE, V, MARIE, S, VINCENT, M.-F, VAN DEN BERGHE, G
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - cerebrospinal fluid; Adenosine Monophosphate - metabolism; Adenosine Monophosphate - urine; adenylosuccinate lyase; Adenylosuccinate Lyase - chemistry; Adenylosuccinate Lyase - deficiency; Adenylosuccinate Lyase - genetics; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - cerebrospinal fluid; Aminoimidazole Carboxamide - metabolism; Aminoimidazole Carboxamide - urine; Biological and medical sciences; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Errors of metabolism; Fibroblasts - enzymology; Fibroblasts - metabolism; Genotype; Homozygote; Humans; Intellectual Disability - genetics; Kinetics; Medical sciences; Metabolic diseases; Metabolism, Inborn Errors - genetics; Miscellaneous hereditary metabolic disorders; Mutation; Mutation, Missense; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - metabolism; Ribonucleosides - cerebrospinal fluid; Ribonucleosides - metabolism; Ribonucleosides - urine; succinyladenosine; succinylaminoimidazolecarboxamide riboside; Temperature; thioredoxin; Time Factors
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.14.2159

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.