AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC

Sandrine Marie; Benedicte Heron; Pierre Bitoun; Therese Timmerman; Georges Van Den Berghe; Marie-Francoise Vincent

doi:10.1086/421475

AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC

Am J Hum Genet. 2004 Jun;74(6):1276-81. doi: 10.1086/421475. Epub 2004 Apr 26.

Authors

Sandrine Marie¹, Benedicte Heron, Pierre Bitoun, Therese Timmerman, Georges Van Den Berghe, Marie-Francoise Vincent

Affiliation

¹ Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology and Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium.

PMID: 15114530
PMCID: PMC1182092
DOI: 10.1086/421475

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Aminoimidazole Carboxamide / analogs & derivatives*
Aminoimidazole Carboxamide / metabolism*
Blindness / congenital
Child, Preschool
Erythrocytes / metabolism
Female
Fibroblasts / drug effects
Humans
Hydroxymethyl and Formyl Transferases / deficiency
Hydroxymethyl and Formyl Transferases / genetics*
Metabolism, Inborn Errors / genetics*
Molecular Sequence Data
Mutation / genetics*
Nucleotide Deaminases / genetics*
Nucleotide Deaminases / metabolism
Phosphoribosylaminoimidazolecarboxamide Formyltransferase
Purines / biosynthesis*
Recombinant Proteins / genetics
Recombinant Proteins / isolation & purification
Recombinant Proteins / metabolism
Ribonucleotides / metabolism*

Substances

Purines
Recombinant Proteins
Ribonucleotides
Aminoimidazole Carboxamide
Hydroxymethyl and Formyl Transferases
Phosphoribosylaminoimidazolecarboxamide Formyltransferase
Nucleotide Deaminases
IMP cyclohydrolase
AICA ribonucleotide

Associated data

GENBANK/BC008879
RefSeq/NT_005403