title: AGXT gene mutations and their influence on clinical heterogeneity of type 1 primary hyperoxaluria.
abstract: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder that is caused by a deficiency of alanine: glyoxylate aminotransferase (AGT), which is encoded by a single copy gene (AGXT). Molecular diagnosis was used in conjunction with clinical, biochemical, and enzymological data to evaluate genotype-phenotype correlation. Twenty-three unrelated, Italian PH1 patients 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 function (group C). All 23 patients were analyzed by using the single-strand conformation polymorphism technique followed by the sequencing of the 11 AGXT exons. Relevant chemistries, including plasma, urine and dialyzate oxalate and glycolate assays, liver AGT activity, and pyridoxine responsiveness, were performed. Both mutant alleles were found in 21 out of 23 patients, and 13 different mutations were recognized in exons 1, 2, 4, and 10. Normalized 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 disease (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 mutation homozygotes had a higher AGT residual activity (P = 0.00001). This study confirms the allelic heterogeneity of the AGXT, which could to some extent be responsible for the phenotypic heterogeneity in PH1.
authors.affiliation: Section of Genetics, Department of Reproductive and Developmental Science, University of Trieste, Trieste, Italy.|Medical Genetics Service, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.affiliation: Section of Genetics, Department of Reproductive and Developmental Science, University of Trieste, Trieste, Italy.
authors.forename: Doroti
authors.initials: D
authors.lastname: Pirulli
authors.affiliation: Department of Biology, University of Trieste, Trieste, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Florian
authors.affiliation: Medical Genetics Service, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Puzzer
authors.affiliation: Section of Genetics, Department of Reproductive and Developmental Science, University of Trieste, Trieste, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Boniotto
authors.affiliation: Section of Genetics, Department of Reproductive and Developmental Science, University of Trieste, Trieste, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
authors.affiliation: Medical Genetics Service, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zezlina
authors.affiliation: Medical Genetics Service, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Spanò
authors.affiliation: Transplant Immunology Service, Ospedale S. Giovanni Battista di Torino, Torino, Italy.
authors.forename: Gina
authors.initials: G
authors.lastname: Mazzola
authors.affiliation: Division of Nephrology and Dialysis, Azienda Ospedaliera Triestina, Trieste, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Savoldi
authors.affiliation: Renal Stones Center, Ospedale Mauriziano Umberto I, Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferrettini
authors.affiliation: Renal Stones Center, Ospedale Mauriziano Umberto I, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Berutti
authors.affiliation: Renal Stones Center, Ospedale Mauriziano Umberto I, Torino, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Petrarulo
authors.affiliation: Renal Stones Center, Ospedale Mauriziano Umberto I, Torino, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Marangella
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D007223:Infant; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology*; D010641:Phenotype; D012720:Severity of Illness Index; D000637:Transaminases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000637:Transaminases; C019635:Alanine-glyoxylate transaminase