AGXT gene mutations and their influence on clinical heterogeneity of type 1 primary hyperoxaluria

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder that is caused by a deficiency of alanine: glyoxylate aminotransferase (AGT), wh ich is encoded by a single copy gene (AGXT). Molecular diagnosis was used i n conjunction with clinical, biochemical, and enzymological data to evaluat e genotype-phenotype correlation. Twenty-three unrelated, Italian PH1 patie nts were studied, 20 of which were grouped according to severe form of PH1 (group A), adult form (group B), and mild to moderate decrease in renal fun ction (group C). All 23 patients were analyzed by using the single-strand c onformation polymorphism technique followed by the sequencing of the 11 AGX T exons. Relevant chemistries, including plasma, urine and dialyzate oxalat e and glycolate assays, liver AGT activity, and pyridoxine responsiveness, were performed. Both mutant alleles were found in 21 out of 23 patients, an d 13 different mutations were recognized in exons 1, 2, 4, and 10. Normaliz ed AGT activity was lower in the severe form than in the adult form (P<0.05 ). Double heterozygous patients presented a lower age at the onset of the d isease (P=0.025), and they were more frequent in group A (75%) than in the group B (14%; P=0.0406). The T444C mutation was more frequent in the severe form (P<0.05), and the opposite was observed for G630A (P<0.05). G630A mut ation homozygotes had a higher AGT residual activity (P=0.00001). This stud y confirms the allelic heterogeneity of the AGXT, which could to some exten t be responsible for the phenotypic heterogeneity in PH1.