Novel molecular defects of the δ-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria

Reiko Akagi, Ryo Shimizu, Kazumichi Furuyama, Manfred O. Doss, Shigeru Sassa

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Cloning and expression of the defective gene for δ-aminolevulinate dehydratase (ALAD) from the second of 2 German patients with ALAD deficiency porphyria (ADP), who had been originally reported by Doss et al. in 1979, were performed. Cloning of cDNAs for the defective ALAD were performed using Epstein-Barr virus (EBV)-transformed lymphoblastoid cells of the proband, and nucleotide sequences of cloned cDNA were determined. Two separate mutations of ALAD cDNA were identified in each ALAD allele. One was G457A, termed 'HI,' resulting in V153M substitution, while the other was a deletion of 2 sequential bases at T818 and C819, termed 'H2,' resulting in a frame shift with a premature stop codon at the amino acid position of 294. Using allele-specific oligonucleotide hybridization, the mother of the proband was shown to have an H1 defect, while using genomic DNA analysis, the father was shown to have an H2 defect. Expression of H1 cDNA in Chinese hamster ovary cells produced an ALAD protein with only a partial activity (10.65% ± 1.80% of the normal), while H2 cDNA encoded no significant protein. These data thus demonstrate that the proband was associated with 2 novel molecular defects of the ALAD gene, 1 in each allele, and account for the extremely low ALAD activity in his erythrocytes (~ 1% of normal).

Original languageEnglish
Pages (from-to)704-708
Number of pages5
JournalHepatology
Volume31
Issue number3
DOIs
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Hepatology

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