title: AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC.
abstract: In a female infant with dysmorphic features, severe neurological defects, and congenital blindness, a positive urinary Bratton-Marshall test led to identification of a massive excretion of 5-amino-4-imidazolecarboxamide (AICA)-riboside, the dephosphorylated counterpart of AICAR (also termed "ZMP"), an intermediate of de novo purine biosynthesis. ZMP and its di- and triphosphate accumulated in the patient's erythrocytes. Incubation of her fibroblasts with AICA-riboside led to accumulation of AICAR, not observed in control cells, suggesting impairment of the final steps of purine biosynthesis, catalyzed by the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase (ATIC). AICAR transformylase was profoundly deficient, whereas the IMP cyclohydrolase level was 40% of normal. Sequencing of ATIC showed a K426R change in the transformylase region in one allele and a frameshift in the other. Recombinant protein carrying mutation K426R completely lacks AICAR transformylase activity.
authors.affiliation: Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology and Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marie
authors.forename: Benedicte
authors.initials: B
authors.lastname: Heron
authors.forename: Pierre
authors.initials: P
authors.lastname: Bitoun
authors.forename: Therese
authors.initials: T
authors.lastname: Timmerman
authors.forename: Georges
authors.initials: G
authors.lastname: Van Den Berghe
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Vincent
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism*; D001766:Blindness / Q000151:congenital; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000172:deficiency / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009709:Nucleotide Deaminases / Q000235:genetics* / Q000378:metabolism; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D011687:Purines / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012265:Ribonucleotides / Q000378:metabolism*
chemical_list: D011687:Purines; D011994:Recombinant Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D009709:Nucleotide Deaminases; C021436:IMP cyclohydrolase; C031143:AICA ribonucleotide