Identification of 5 novel mutations in the AGXT gene

Abstract

In order to identify additional genotypes in primary hyperoxaluria type 1, we sequenced the AGXT genes of 9 patients. We report 5 new mutations. Three are splice‐site mutations situated at the end of intron 4 and 8 (647‐1G>A, 969‐1G>C, 969‐3C>G), one is a missense mutation in exon 5 (D183N), and one is a short duplication in exon 2 (349ins7). Their consequence is always a lack of enzymatic activity of the Alanine‐Glyoxylate Aminotransferase (AGT); for 4 of them, we were able to deduce that they were associated to the absence of AGT protein. These mutations are rare, as they have been found on one allele in our study (except 969‐3C>G present in 2 unrelated families), and have not been previously reported. Hum Mutat 15:577, 2000. © 2000 Wiley‐Liss, Inc.

Primary hyperoxaluria in a compound heterozygote infant

“…A trial with pyridoxine, the cofactor of AGT enzyme for 3 to 6 months may lead to significant reduction in oxalate excretion in a small proportion of patients. [5] The case we treated shows the coexistence of two mutations of the AGXT gene recently reported, [7,8] serves to remind the importance of the association of nephrocalcinosis and urolithiasis as key diagnostic manifestations of PH1 and confirms the severe course of the disease when it presents in infancy.…”

“…So far, a total of 146 mutations have been described on the AGXT gene. [6] The two found in our patient were c.33dupC [7] (formerly c.33_34insC) and c.847-3C>G [8] . The first one is quite common in PH1 patients, and when present in homozygosis, AGT activity is very low.…”

“…To our knowledge, it has only been reported in 2 cases. [8] As an inborn error, AGT dysfunction is present at birth, but clinical manifestations may appear from infancy to adulthood because of the great heterogeneity of the disease. Even siblings with identical mutation may manifest a completely different phenotype.…”

Primary hyperoxaluria in a compound heterozygote infant

“…A trial with pyridoxine, the cofactor of AGT enzyme for 3 to 6 months may lead to significant reduction in oxalate excretion in a small proportion of patients. [5] The case we treated shows the coexistence of two mutations of the AGXT gene recently reported, [7,8] serves to remind the importance of the association of nephrocalcinosis and urolithiasis as key diagnostic manifestations of PH1 and confirms the severe course of the disease when it presents in infancy.…”

“…So far, a total of 146 mutations have been described on the AGXT gene. [6] The two found in our patient were c.33dupC [7] (formerly c.33_34insC) and c.847-3C>G [8] . The first one is quite common in PH1 patients, and when present in homozygosis, AGT activity is very low.…”

“…To our knowledge, it has only been reported in 2 cases. [8] As an inborn error, AGT dysfunction is present at birth, but clinical manifestations may appear from infancy to adulthood because of the great heterogeneity of the disease. Even siblings with identical mutation may manifest a completely different phenotype.…”

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1

“…24,25 However, the I244T represented 26%, which reflects on the ethnicity of our population, as it is predominant in Mediterranean countries. 26,27 No phenotype-genotype correlation could be established in our study.…”

Importance of Assessing Compliance with Conservative Treatment of Primary Hyperoxaluria Type 1: A Case Report of a Patient with I244T/c.969-3C>G Mutation

“…5,8 Moreover, she was heterozygous, carrying a splice-site (null) mutation in intron 8, c.969-3C>G, a condition that had been reported in only 3 other, unrelated patients. 9,10 As far as we know, this is a unique case of a patient with a I244T/null mutation diagnosed after the neonatal period maintaining normal renal function and remaining asymptomatic, who has achieved outstanding therapeutic success. The purpose of this case report is to emphasize the importance of assessing full therapeutic compliance with PH1 conservative treatment and to raise awareness of the possibilities that might cause…”

Primary hyperoxaluria in a compound heterozygote infant

“…A trial with pyridoxine, the cofactor of AGT enzyme for 3 to 6 months may lead to significant reduction in oxalate excretion in a small proportion of patients. [5] The case we treated shows the coexistence of two mutations of the AGXT gene recently reported, [7,8] serves to remind the importance of the association of nephrocalcinosis and urolithiasis as key diagnostic manifestations of PH1 and confirms the severe course of the disease when it presents in infancy.…”

“…So far, a total of 146 mutations have been described on the AGXT gene. [6] The two found in our patient were c.33dupC [7] (formerly c.33_34insC) and c.847-3C>G [8] . The first one is quite common in PH1 patients, and when present in homozygosis, AGT activity is very low.…”

“…To our knowledge, it has only been reported in 2 cases. [8] As an inborn error, AGT dysfunction is present at birth, but clinical manifestations may appear from infancy to adulthood because of the great heterogeneity of the disease. Even siblings with identical mutation may manifest a completely different phenotype.…”

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1

“…24,25 However, the I244T represented 26%, which reflects on the ethnicity of our population, as it is predominant in Mediterranean countries. 26,27 No phenotype-genotype correlation could be established in our study.…”

Importance of Assessing Compliance with Conservative Treatment of Primary Hyperoxaluria Type 1: A Case Report of a Patient with I244T/c.969-3C>G Mutation

“…5,8 Moreover, she was heterozygous, carrying a splice-site (null) mutation in intron 8, c.969-3C>G, a condition that had been reported in only 3 other, unrelated patients. 9,10 As far as we know, this is a unique case of a patient with a I244T/null mutation diagnosed after the neonatal period maintaining normal renal function and remaining asymptomatic, who has achieved outstanding therapeutic success. The purpose of this case report is to emphasize the importance of assessing full therapeutic compliance with PH1 conservative treatment and to raise awareness of the possibilities that might cause…”

Primary hyperoxaluria in a compound heterozygote infant

“…A trial with pyridoxine, the cofactor of AGT enzyme for 3 to 6 months may lead to significant reduction in oxalate excretion in a small proportion of patients. [5] The case we treated shows the coexistence of two mutations of the AGXT gene recently reported, [7,8] serves to remind the importance of the association of nephrocalcinosis and urolithiasis as key diagnostic manifestations of PH1 and confirms the severe course of the disease when it presents in infancy.…”

“…So far, a total of 146 mutations have been described on the AGXT gene. [6] The two found in our patient were c.33dupC [7] (formerly c.33_34insC) and c.847-3C>G [8] . The first one is quite common in PH1 patients, and when present in homozygosis, AGT activity is very low.…”

“…To our knowledge, it has only been reported in 2 cases. [8] As an inborn error, AGT dysfunction is present at birth, but clinical manifestations may appear from infancy to adulthood because of the great heterogeneity of the disease. Even siblings with identical mutation may manifest a completely different phenotype.…”

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1

“…24,25 However, the I244T represented 26%, which reflects on the ethnicity of our population, as it is predominant in Mediterranean countries. 26,27 No phenotype-genotype correlation could be established in our study.…”

Importance of Assessing Compliance with Conservative Treatment of Primary Hyperoxaluria Type 1: A Case Report of a Patient with I244T/c.969-3C>G Mutation

“…5,8 Moreover, she was heterozygous, carrying a splice-site (null) mutation in intron 8, c.969-3C>G, a condition that had been reported in only 3 other, unrelated patients. 9,10 As far as we know, this is a unique case of a patient with a I244T/null mutation diagnosed after the neonatal period maintaining normal renal function and remaining asymptomatic, who has achieved outstanding therapeutic success. The purpose of this case report is to emphasize the importance of assessing full therapeutic compliance with PH1 conservative treatment and to raise awareness of the possibilities that might cause…”