Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.

[primary hyperoxaluria type 1]

The gene encoding the liver -specific peroxisomal enzyme alanine :glyoxylate aminotransferase (AGT , EC . 2 .6 .1 .44 ) exists as two common polymorphic variants termed the "major " and "minor " alleles . The P 11 L amino acid replacement encoded by the minor allele creates a hidden N-terminal mitochondrial targeting sequence , the unmasking of which occurs in the hereditary calcium oxalate kidney stone disease primary hyperoxaluria type 1 (PH 1 ). This unmasking is due to the additional presence of a common disease-specific G 170 R mutation , which is encoded by about one third of PH 1 alleles . The P 11 L and G 170 R replacements interact synergistically to reroute AGT to the mitochondria where it can not fulfill its metabolic role (i .e . glyoxylate detoxification ) effectively . In the present study , we have reinvestigated the consequences of the interaction between P 11 L and G 170 R in stably transformed CHO cells and have studied for the first time whether a similar synergism exists between P 11 L and three other mutations that segregate with the minor allele (i .e . I 244 T , F 152 I , and G 41 R ). Our investigations show that the latter three mutants are all able to unmask the cryptic P 11 L -generated mitochondrial targeting sequence and , as a result , all are mistargeted to the mitochondria . However , whereas the G 170 R , I 244 T , and F 152 I mutants are able to form dimers and are catalytically active , the G 41 R mutant aggregates and is inactive . These studies open up the possibility that all PH 1 mutations , which segregate with the minor allele , might also lead to the peroxisome-to -mitochondrion mistargeting of AGT , a suggestion that has important implications for the development of treatment strategies for PH 1 .

Diseases
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Diseases presenting "common polymorphic variants" symptom

primary hyperoxaluria type 1

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