Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBSgene

Acute intermittent porphyria (AIP) is a low-penetrant, autosomal dominant d isorder caused by mutations in the HMBS gene. The gene is transcribed from two promoters to produce ubiquitous and erythroid isoforms of porphobilinog en deaminase, which differ only at their NH2 ends. In the classical form of AIP, both isoforms are deficient, but about 5% of families have the non-er ythroid variant in which only the ubiquitous isoform is affected. Previousl y identified mutations in this variant have been within or close to the cod ing region of exon 1 of the HMBS gene, the only exon that is expressed sole ly in the ubiquitous isoform. Here, we describe mutations in the ubiquitous promoter (-154delG) and in exon 3 (41delA) that cause the non-erythroid va riant. Reporter gene and electrophoretic mobility shift assays show that th e G nucleotide at position -154, the most 5' of several transcription-initi ation sites in the ubiquitous HMBS promoter, which lies immediately 3' to a transcription-factor IIB binding motif, is essential for normal transcript ion. The frameshift mutation in exon 3 introduces a stop codon into mRNA fo r the ubiquitous isoform only. Our investigations identify two new mechanis ms for production of the non-erythroid variant of AIP and demonstrate that mutational analysis for diagnosis of this variant needs to include wider re gions of the HMBS gene than indicated by previous reports. Furthermore, the y show that deletion of one of several transcription initiation sites in th e promoter of a housekeeping gene that lacks both TATA and initiator elemen ts can produce disease.