Human Molecular Genetics, 2000, Vol. 9, No. 14 2159-2165
© 2000 Oxford University Press
Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency
Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology, and Université Catholique de Louvain, B-1200 Brussels, Belgium
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 
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.
+ To whom correspondence should be addressed. Tel: +32 2 764 7539; Fax: +32 2 764 75 98; Email: vandenberghe@bchm.ucl.ac.be
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Rebora, B. Laloo, and B. Daignan-Fornier Revisiting Purine-Histidine Cross-Pathway Regulation in Saccharomyces cerevisiae: A Central Role for a Small Molecule Genetics, May 1, 2005; 170(1): 61 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sivendran, D. Patterson, E. Spiegel, I. McGown, D. Cowley, and R. F. Colman Two Novel Mutant Human Adenylosuccinate Lyases (ASLs) Associated with Autism and Characterization of the Equivalent Mutant Bacillus subtilis ASL J. Biol. Chem., December 17, 2004; 279(51): 53789 - 53797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Holder-Espinasse, S Marie, G Bourrouillou, I Ceballos-Picot, M-C Nassogne, L Faivre, J Amiel, A Munnich, M-F Vincent, and V Cormier-Daire Towards a suggestive facial dysmorphism in adenylosuccinate lyase deficiency? J. Med. Genet., June 1, 2002; 39(6): 440 - 442. [Full Text] [PDF]
|
|