Acute intermittent porphyria: a single-base deletion and a nonsense mutation in the human hydroxymethylbilane synthase gene, predicting truncations of the enzyme polypeptide.
Acute intermittent porphyria (AIP) is an autosomal-dominant inborn error of metabolism that results from the half-normal activity of the third enzyme in the heme biosynthetic pathway, hydroxymethylbilane synthase (HMB-synthase). AIP is an ecogenetic condition, since the life-threatening acute attacks are precipitated by various factors, including drugs, alcohol, fasting, and certain hormones. Biochemical diagnosis is problematic, and the identification of mutations in the HMB-synthase gene provides accurate detection of presymptomatic heterozygotes, permitting avoidance of the acute precipitating factors. By direct solid-phase sequencing, two mutations causing AIP were identified, an adenine deletion at position 629 in exon 11(629delA), which alters the reading frame and predicts premature truncation of the enzyme protein after amino acid 255, and a nonsense mutation in exon 12 (R225X). These mutations were confirmed by either restriction enzyme analysis or family studies of symptomatic patients, permitting accurate presymptomatic diagnosis of affected relatives.
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.
G Y
GY
Lee
K H
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Astrin
R J
RJ
Desnick
D001482:Base Composition; D001483:Base Sequence; D018389:Codon, Nonsense; D004262:DNA Restriction Enzymes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017118:Porphyria, Acute Intermittent / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D017384:Sequence Deletion
D018389:Codon, Nonsense; D010455:Peptides; D011163:Hydroxymethylbilane Synthase; D004262:DNA Restriction Enzymes