Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene

Purpose: To identify mutations in families with acute intermittent porphyri a, an autosomal dominant inborn error of metabolism that results from the h alf-normal activity of the third enzyme in the heme biosynthetic pathway, h ydroxymethylbilane synthase. Methods: Mutations were identified by direct s olid phase sequencing. Results: Two novel missense mutations E80G and T78P and three previously reported mutations, R173W, G111R, and the splice site lesion, IVS1(+1), were detected, each in an unrelated proband. The causalit y of the novel missense mutations was demonstrated by expression studies. C onclusion: These findings provide for the precise diagnosis of carriers in these families and further expand the molecular heterogeneity of AIP.