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AGXT Gene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria

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AGXT Gene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria J Am Soc Nephrol 12: 2072–2079, 2001 AGXT Gene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria ANTONIO AMOROSO,*† DOROTI PIRULLI,* FIORELLA FLORIAN,‡ DANIELA PUZZER,† MICHELE BONIOTTO,* SERGIO CROVELLA,* SILVIA ZEZLINA,† ANDREA SPANO` ,† GINA MAZZOLA,§ SILVANA SAVOLDI,࿣ CRISTINA FERRETTINI,¶ SILVIA BERUTTI,¶ MICHELE PETRARULO,¶ and MARTINO MARANGELLA¶ *Section of Genetics, Department of Reproductive and Developmental Science, University of Trieste, Trieste, Italy; †Medical Genetics Service, IRCCS Burlo Garofolo, Trieste, Italy; ‡Department of Biology, University of Trieste, Trieste, Italy; §Transplant Immunology Service, Ospedale S. Giovanni Battista di Torino, Torino, Italy; ࿣Division of Nephrology and Dialysis, Azienda Ospedaliera Triestina, Trieste, Italy; and ¶Renal Stones Center, Ospedale Mauriziano Umberto I, Torino, Italy. Abstract. Primary hyperoxaluria type 1 (PH1) is an autosomal were performed. Both mutant alleles were found in 21 out of recessive disorder that is caused by a deficiency of alanine: 23 patients, and 13 different mutations were recognized in glyoxylate aminotransferase (AGT), which is encoded by a exons 1, 2, 4, and 10. Normalized AGT activity was lower in single copy gene (AGXT). Molecular diagnosis was used in the severe form than in the adult form (P Ͻ 0.05). Double conjunction with clinical, biochemical, and enzymological data heterozygous patients presented a lower age at the onset of the to evaluate genotype-phenotype correlation. Twenty-three un- disease (P ϭ 0.025), and they were more frequent in group A related, Italian PH1 patients were studied, 20 of which were (75%) than in the group B (14%; P ϭ 0.0406). The T444C grouped according to severe form of PH1 (group A), adult mutation was more frequent in the severe form (P Ͻ 0.05), and form (group B), and mild to moderate decrease in renal func- the opposite was observed for G630A (P Ͻ 0.05). G630A tion (group C). All 23 patients were analyzed by using the mutation homozygotes had a higher AGT residual activity (P single-strand conformation polymorphism technique followed ϭ 0.00001). This study confirms the allelic heterogeneity of by the sequencing of the 11 AGXT exons. Relevant chemistries, the AGXT, which could to some extent be responsible for the including plasma, urine and dialyzate oxalate and glycolate phenotypic heterogeneity in PH1. assays, liver AGT activity, and pyridoxine responsiveness, Primary hyperoxaluria type 1 (PH1; OMIM: 259900) is a rare progressive storage of CaOx crystals, causing a syndrome autosomal recessive disorder that is characterized by the im- referred to as systemic oxalosis (5). paired hepatic detoxification of glyoxylate. It is caused by a The clinical setting of the disease is highly heterogeneous deficiency of alanine:glyoxylate aminotransferase (AGT; EC with respect to age at onset, type of presentation, severity of 2.6.1.44), which catalyzes the transamination of glyoxylate to hyperoxaluria, residual enzymatic activity, and progression to glycine (1). This disorder leads to the endogenous overproduc- renal insufficiency (6). Most patients suffered from recurrent tion of oxalate and glycolate, resulting in oxalic and glycolic episodes of nephrolithiasis in childhood or adolescence; the hyperacidurias, which are the hallmarks of the disease (2,3). infantile form of oxalosis is diagnosed only in few cases, a The pathophysiology of hyperoxaluria is a result of the low factor that often leads to death for renal failure during the first degree of solubility of the calcium oxalate (CaOx) that pro- months of life. An increasing number of patients are diagnosed duces urolithiasis and/or nephrocalcinosis, often leading to only in adulthood, usually after a long-standing history of renal failure. The loss of the renal function generally increases recurrent nephrolithiasis and sometimes after starting dialysis the oxalate plasma levels, and it induces calcium oxalate over- treatment or after a kidney transplant (6). saturation in the body fluids (4). In many tissues, this causes a The AGT enzyme is encoded by a single copy gene (AGXT), consisting of 11 exons, ranging from 65 bp to 407 bp, and spanning over a 10 Kb DNA segment in the 2q37.3 human Received April 21, 2000. Accepted April 26, 2001. region (7). AGT is a 392-amino acid protein with a molecular Correspondence to Dr. Antonio Amoroso, Servizio di Genetica—IRCCS Burlo weight of 43 kD (8). From the cytosol, where it has a homo- Garofolo, Via dell’Istria 65/1 - 34137 Trieste - Italy. Phone: ϩ39 040 3785275; Fax: ϩ39 040 3785210; E-mail: [email protected] dimeric structure, it is then imported into the peroxisomes, 1046-6673/1210-2072 where it detoxifies the glyoxylate by using pyridoxal-5-phos- Journal of the American Society of Nephrology phate as a cofactor (1). Copyright © 2001 by the American Society of Nephrology Although the enzyme is normally located in the peroxi- J Am Soc Nephrol 12: 2072–2079, 2001 Genotype-Phenotype in Primary Hyperoxaluria Type 1 2073 somes, a small AGT amount (5%) can also be found in the removal of the same chemistries were measured in the other patients mitochondria (9), where the enzyme does not function (6). on renal replacement therapy. So far, seven polymorphisms and 35 mutations have been The results belonging to patients who were suspected of having identified in the AGXT gene by using several technical ap- PH1 (in any of the above groups) were compared with reference proaches (10–22). values belonging to normal individuals or patients undergoing dialysis for oxalosis-unrelated nephropathies. PH1 was, therefore, diagnosed The disease is caused by homozygous point mutations or by when both the levels of oxalate and of glycolate were higher than the compound heterozygous in two different point mutations. highest reference range (Table 1). Polymorphic sequences have also been proven to combine with We then analyzed the response of 20 patients to pyridoxine by two haplotypes that were identified in the normal white pop- repeating the same assays after a 10 to 30 mg/kg per d pyridoxine ulation. The major (80% frequency) and the minor (20% fre- treatment that lasted 1 month. We arbitrarily defined the positive quency) haplotype present a combination of three polymor- response as a normalization or a 50% decrease in both oxalate and phisms: 74 bp duplication within the first intron (12,18) and glycolate levels in plasma and urine. C154T and A1142G point mutations, which specify Pro11Leu Liver biopsies were performed to test the AGT and gamma-glu- and Ile340Met amino acid substitutions, respectively (9). The tamyl transferase (GGT) activity. At the time of biopsy, the patients normal minor haplotype is responsible for a 5% mistargeting of had been off the pyridoxine treatment for an entire month. Clinical the AGT to the mitochondria; the mistargeting then rises to and biochemical details are summarized in Table 2. 90% when the minor haplotype is associated to G630A (Gly170Arg amino acid substitution) (19,23). Biochemical Procedures In this article, we report the clinical findings and the AGXT The levels of oxalate and glycolate in plasma, urine, and dialysis mutations of 23 unrelated Italian PH1 patients. To establish fluids were determined by HPLC procedures, as specified elsewhere genotype-phenotype correlations, we used a molecular diagno- (24). Specimens from hepatic biopsies were analyzed for AGT and sis associated to clinical, biochemical, and enzymological data. GGT by means of a HPLC-based microassay (25). The GFR mea- surements, relating to patients with maintained renal function, were Materials and Methods carried out contemporaneously with the plasma and urine assaying for oxalate, glycolate, and L-glycerate during the last visit to our center. Patients As outlined previously, the reference ranges derive from the values of In this study, we considered 23 unrelated patients from 11 different normal individuals or patients undergoing dialysis for oxalosis-unre- Italian regions; 14 were men, and 9 were women. Ages ranged from lated nephropathies; these findings were published elsewhere and are Ϯ 1 to 50 yr (mean, 25.3 16.6 yr). Some of the relatives of 10 patients summarized in Table 1 (26,27). were also analyzed for the genetic study. Eight of the 23 patients had a normal or only mildly reduced renal function, 7 were on regular dialysis treatment, 3 received a kidney graft, and 5 had undergone a Molecular Approach combined liver-kidney transplant. The DNA extraction and the in vitro amplification were performed Based on the age at onset, 1 patient had an infantile oxalosis, 7 had as described previously (28). Initially, the PCR products were ana- an adult form, and the disease was diagnosed during adolescence in 15 lyzed by using the technique of the single-strand conformation poly- patients. According to the clinical data, 4 patients had renal failure morphism (SSCP) under standard conditions (29). The samples show- associated to nephrocalcinosis, whereas 19 had recurrent nephrolithi- ing an abnormal electrophoretic pattern were analyzed by direct asis. When analyzing the renal function among our 23 patients, we sequencing of both strands using the BigDye Terminator Cycle Se- saw that 8 patients were diagnosed with PH1 after they had started quencing Kit (PE Biosystems, Foster City, CA) on an automated ABI dialysis and that 2 were diagnosed after a kidney transplantation. For PRISM 310 Sequencer (PE Biosystems) (10). For the unrecognized eight patients, those with maintained renal function, the classification mutation, we performed a mutation analysis using direct sequencing of PH1 in terms of clinical data and diagnosis was made by assaying together with SSCP. For patient 20 and patient 23, we performed the plasma and the urine for oxalate, glycolate, and L-glycerate in at direct sequencing of all 11 AGXT exons. The co-inheritance of the least two separate sample collections. Plasma levels and dialysis mutations with the major or minor haplotype was checked by ampli- Table 1.
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