Identification and characterization of two novel mutations that produce acute intermittent porphyria: A 3-base deletion (841-843delGGA) and a missense mutation (T35M).

ABSTRACT

A partial deficiency of Porphobilinogen deaminase (PBGD) is responsible for acute intermittent porphyria (AIP). AIP is inherited in an autosomal dominant fashion, and the prevalence in the Argentinean population is about 1125,000. Here, two new mutations and two previously reported were found in the PBGD gene in 22 Argentinean AIP patients corresponding to 8 different families. To screen for AIP mutations in symptomatic patients, genomic DNA isolated was amplified in 6 PCR reactions, then all coding exons and flanking intronic regions were sequenced. The novel mutations are 841-843delGGA in exon 14, which results in the loss of glycine-281 (G281del), and one 104C>T point mutation in the exon 4 (T35M). To further characterize both novel mutations, the pKK-PBGD construct for the mutant alleles were expressed in E. coli, the enzymatic activity of the recombinant proteins were 1% and 4% of the mean level expressed by the normal allele for 841-843delGGA and T35M, respectively. Hum Mutat 16373, 2000.