| #608688 | ||||||||||
| AICAR TRANSFORMYLASE/IMP CYCLOHYDROLASE DEFICIENCY | ||||||||||
| Alternative titles; symbols | ||||||||||
| ATIC DEFICIENCY AICA-RIBOSURIA DUE TO ATIC DEFICIENCY | ||||||||||
| Phenotype Gene Relationships | ||||||||||
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| Clinical Synopsis | ||||||||||
| TEXT | ||||||||||
| A number sign (#) is used with this entry because the phenotype can be caused by mutation in the ATIC gene (601731), encoding the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase. | ||||||||||
| Clinical Features | ||||||||||
| Marie et al. (2004) described a 4-year-old girl who presented with a devastating neurologic picture involving profound mental retardation, epilepsy, dysmorphic features, and congenital blindness. Dysmorphic features included cutaneous dimples on the extensor side of knees, elbows, and shoulders. By age 12 months, bilateral atrophic pigmented chorioretinal macular lesions had developed with optic atrophy, and abnormal electroretinograms and visual evoked potentials were observed. Chromatograms of the patient's urine revealed 3 peaks seen neither in control individuals' urine nor in that of ADSL-deficient patients (608222). The major peak was identified as 5-amino-4-imidazolecarboxamide riboside (AICA-riboside), on the basis of a positive Bratton-Marshall test, spectral analysis, and spiking with the authentic compound. AICA-riboside is the nucleoside corresponding to AICAR (AICA-ribotide, also termed ZMP), an intermediate of the de novo purine biosynthetic pathway. AICA-riboside is formed by dephosphorylation of AICAR, most likely by IMP-GMP 5-prime-nucleotidase. When Marie et al. (2004) incubated fibroblasts from their patient with AICA-riboside, they observed 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; 601731). AICAR transformylase was profoundly deficient, whereas the IMP cyclohydrolase level was 40% of normal. The presence of massive amounts of AICA-riboside in the patient's urine and the accumulation of AICAR and its derivatives in her erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a clear indication of deficiency in the enzyme that utilizes this intermediate de novo purine biosynthesis, the bifunctional enzyme encoded by the ATIC gene. | ||||||||||
| Molecular Genetics | ||||||||||
| Marie et al. (2004) performed sequence analysis of the ATIC gene in their patient with AICA-ribosuria and found compound heterozygosity for mutations. A missense mutation (K426R; 601731.0001) in the transformylase region was inherited from the father, and a frameshift mutation caused by a duplication/deletion event (601731.0002) was inherited from the mother. The missense mutation was located within a conserved region implicated in the binding of a potassium ion in the avian protein (Greasley et al., 2001). This potassium ion has been proposed to play a key role in stabilization of the tertiary structure of the protein. In expression studies, recombinant protein carrying the K426R mutation completely lacked AICAR-TF activity but still showed IMP-CH activity. | ||||||||||
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