MOLECULAR-BASIS OF ACUTE INTERMITTENT PORPHYRIA - MUTATIONS AND POLYMORPHISMS IN THE HUMAN HYDROXYMETHYLBILANE SYNTHASE GENE

Acute intermittent porphyria (AIP) is an autosomal dominant inborn err or of metabolism that results from the half normal activity of the thi rd enzyme in the heme biosynthetic pathway, hydroxymethylbilane syntha se (HMB-synthase). AIP is an ecogenetic condition, with life-threateni ng acute attacks precipitated by various factors including drugs, alco hol, fasting, and certain hormones. Biochemical diagnosis is problemat ic and the identification of mutations in the HMB synthase gene provid es ac curate detection of presymptomatic heterozygotes, permitting avo idance of the acute precipitating factors. Two HMB synthase isozymes a re encoded by the HMB synthase gene: one unique to erythroid cells and the other a housekeeping isozyme present in all cells. These two isoz ymes arise from a single gene by alternative splicing. The recent isol ation of the cDNAs and entire genomic sequence encoding the HMB syntha se isozymes has facilitated the detection of diagnostically useful int ragenic polymorphisms and disease-causing mutations, Of the 36 mutatio ns identified to date, most caused the classic form of AIP. These muta tions included small deletions and insertions, point mutations and RNA splice junction alterations and resulted in the half normal activity of both the erythroid specific and house keeping isozymes. Most AIP mu tations were private; however, certain mutations were frequently found in Dutch (R116W) and Swedish (W198X) AIP families. A variant form of AIP, in which patients have normal erythroid activity, but half-normal activity of the housekeeping isozyme, resulted from two mutations at the exon 1/intron 1 boundary, each altering splicing of the hepatic sp ecific transcript. In addition, 10 polymorphisms in the HMB synthase g ene have been identified that are useful for the diagnosis of presympt omatic AIP heterozygotes in families whose specific mutations have not been determined. (C) 1994 Wiley-Liss, Inc.