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J Clin Invest. 1992 May;89(5):1431-7.

Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria.

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Rockefeller University, New York 10021.


Cloning and expression of the defective genes for delta-aminolevulinate dehydratase (ALAD) from a patient with inherited ALAD deficiency porphyria (ADP) were carried out. Cloning of cDNAs for the defective ALAD were performed from EBV-transformed lymphoblastoid cells of the proband, and nucleotide sequences were determined. Two separate point mutations resulting in a single amino acid change in each ALAD allele were identified. One, C718----T, termed 'G1', occurred in the allele within the substrate-binding site, producing an Arg240----Trp substitution; the other, G820----A, termed 'G2', occurred downstream of this site in the other allele, resulting in an Ala274----Thr substitution. Using the reverse transcription-polymerase chain reaction, the mother, the brother, and the sister were shown to have the G1 defect. Expression of the G1 cDNA in Chinese hamster ovary cells produced ALAD protein with little activity; the G2 cDNA produced the enzyme with approximately 50% normal activity. Pulse-labeling studies demonstrated that the G1 enzyme had a normal half life, while the G2 enzyme had a markedly decreased half life. These data thus define the separate point mutations in each ALAD allele, as well as the altered properties of the two enzymic proteins encoded by the mutant genes in a patient with ADP.

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