scholarly journals Human peroxisomal l-alanine: glyoxylate aminotransferase. Evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon

1990 ◽  
Vol 268 (2) ◽  
pp. 517-520 ◽  
Author(s):  
Y Takada ◽  
N Kaneko ◽  
H Esumi ◽  
P E Purdue ◽  
C J Danpure
Keyword(s):  
Point Mutation ◽  
Signal Sequence ◽  
Primary Hyperoxaluria ◽  
Initiation Codon ◽  
Mitochondrial Targeting ◽  
Primary Hyperoxaluria Type 1 ◽  
Targeting Signal ◽  
Glyoxylate Aminotransferase ◽  
Hyperoxaluria Type

The amino acid sequence of human hepatic peroxisomal L-alanine: glyoxylate aminotransferase 1 (AGTI) deduced from cDNA shows 78% sequence identity with that of rat mitochondrial AGTI, but lacks the N-terminal 22 amino acids (the putative mitochondrial targeting signal). In humans this signal appears to have been deleted during evolution by a point mutation of the initiation codon ATG to ATA. These data suggest that the targeting defect in primary hyperoxaluria type 1, in which AGT1 is diverted from the peroxisomes to the mitochondria, could be due to a point mutation that reintroduces all or part of the mitochondrial signal sequence.

scholarly journals Late Diagnosis of Primary Hyperoxaluria by Crystals in the Bone Marrow!

2015 ◽  
Vol 1 (1) ◽  
pp. napoc.2015.1467
Author(s):  
Mohammed Hameed ◽  
Kashif Eqbal ◽  
Beena Nair ◽  
Alexander Woywodt ◽  
Aimun Ahmed
Keyword(s):  
Autosomal Recessive ◽  
Primary Hyperoxaluria ◽  
Primary Hyperoxaluria Type 1 ◽  
Delay In Diagnosis ◽  
The Poor ◽  
Stage Renal Disease ◽  
End Stage ◽  
Glyoxylate Aminotransferase ◽  
Hyperoxaluria Type

Primary hyperoxaluria type 1 (PH1) is a rare, inherited, autosomal recessive, metabolic disorder caused by a deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT). We describe here a case of a 57-year-old man with End Stage Renal Disease, where the late age of presentation of PH T1 due to marked heterogeneity of disease expression caused a delay in diagnosis, and we discuss the causes of the poor outcome typical of this condition

Fetal liver alanine: Glyoxylate aminotransferase and the prenatal diagnosis of primary hyperoxaluria type 1

1989 ◽  
Vol 9 (4) ◽  
pp. 271-281 ◽  
Author(s):  
Christopher J. Danpure ◽  
Patricia R. Jennings ◽  
Richard J. Penketh ◽  
Pauline J. Wise ◽  
Penelope J. Cooper ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Fetal Liver ◽  
Primary Hyperoxaluria ◽  
Primary Hyperoxaluria Type 1 ◽  
Primary Hyperoxaluria Type ◽  
Glyoxylate Aminotransferase ◽  
Hyperoxaluria Type

scholarly journals Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.

1990 ◽  
Vol 111 (6) ◽  
pp. 2341-2351 ◽  
Author(s):  
P E Purdue ◽  
Y Takada ◽  
C J Danpure
Keyword(s):  
Normal Population ◽  
Primary Hyperoxaluria ◽  
Alpha Helix ◽  
Primary Hyperoxaluria Type 1 ◽  
Peroxisomal Enzyme ◽  
Primary Hyperoxaluria Type ◽  
Oligonucleotide Hybridization ◽  
Glyoxylate Aminotransferase ◽  
Hyperoxaluria Type

We have previously shown that in some patients with primary hyperoxaluria type 1 (PH1), disease is associated with mistargeting of the normally peroxisomal enzyme alanine/glyoxylate aminotransferase (AGT) to mitochondria (Danpure, C.J., P.J. Cooper, P.J. Wise, and P.R. Jennings. J. Cell Biol. 108:1345-1352). We have synthesized, amplified, cloned, and sequenced AGT cDNA from a PH1 patient with mitochondrial AGT (mAGT). This identified three point mutations that cause amino acid substitutions in the predicted AGT protein sequence. Using PCR and allele-specific oligonucleotide hybridization, a range of PH1 patients and controls were screened for these mutations. This revealed that all eight PH1 patients with mAGT carried at least one allele with the same three mutations. Two were homozygous for this allele and six were heterozygous. In at least three of the heterozygotes, it appeared that only the mutant allele was expressed. All three mutations were absent from PH1 patients lacking mAGT. One mutation encoding a Gly----Arg substitution at residue 170 was not found in any of the control individuals. However, the other two mutations, encoding Pro----Leu and Ile----Met substitutions at residues 11 and 340, respectively, cosegregated in the normal population at an allelic frequency of 5-10%. In an individual homozygous for this allele (substitutions at residues 11 and 340) only a small proportion of AGT appeared to be rerouted to mitochondria. It is suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import.

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