RESUMO
Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.
Assuntos
Centros Médicos Acadêmicos , Pesquisa Biomédica , Humanos , IncertezaRESUMO
Mutations in the alanine-glyoxylate amino transferase gene (AGXT) are responsible for primary hyperoxaluria type I, a rare disease characterized by excessive hepatic oxalate production that leads to renal failure. We generated a null mutant mouse by targeted mutagenesis of the homologous gene, Agxt, in embryonic stem cells. Mutant mice developed normally, and they exhibited hyperoxaluria and crystalluria. Approximately half of the male mice in mixed genetic background developed calcium oxalate urinary stones. Severe nephrocalcinosis and renal failure developed after enhancement of oxalate production by ethylene glycol administration. Hepatic expression of human AGT1, the protein encoded by AGXT, by adenoviral vector-mediated gene transfer in Agxt(-/-) mice normalized urinary oxalate excretion and prevented oxalate crystalluria. Subcellular fractionation and immunofluorescence studies revealed that, as in the human liver, the expressed wild-type human AGT1 was predominantly localized in mouse hepatocellular peroxisomes, whereas the most common mutant form of AGT1 (G170R) was localized predominantly in the mitochondria.
Assuntos
Adenoviridae/genética , Hiperoxalúria Primária/enzimologia , Hiperoxalúria Primária/genética , Transaminases/deficiência , Transaminases/metabolismo , Alelos , Animais , Fenômenos Químicos , Físico-Química , Modelos Animais de Doenças , Feminino , Técnicas de Transferência de Genes , Terapia Genética , Humanos , Hiperoxalúria Primária/patologia , Masculino , Camundongos , Camundongos Knockout , Transaminases/genética , Cálculos da Bexiga Urinária/patologiaRESUMO
We report the molecular characterization of a ring X chromosome that was transmitted from a mother to a male who has short stature and minor dysmorphic features. This represents only the second reported ring X chromosome in a male. The ring is derived from breakage within the Xp pseudoautosomal region (PAR) and just proximal to the Xq PAR. The total amount of deleted material is 700-900 kb DNA and includes six known transcribed genes. Interestingly, SHOX, a gene implicated in short stature, is not deleted from the ring chromosome. Possible pathogenetic explanations for the patient's clinical features include insufficient dosage of deleted genes, a position effect on SHOX expression, and cell death during development because of ring chromosome nondisjunction. The findings are also relevant to observations made of "complete" ring chromosomes.
