Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disea se caused by a decreased activity of hydroxymethylbilane synthase (HMBS). R egarding the abnormalities of the NMBS gene, many different mutations have been reported worldwide; however, few families from Japan have been studied . In this work, we investigated the presence of mutations in two unrelated Japanese patients with AIP. Mutational analysis was performed using the pol ymerase chain reaction-single strand conformation polymorphism (SSCP) metho d, followed by DNA sequencing. Reliable restriction enzyme cleavage assays were also established for the pedigree analyses. Unique SSCP patterns were noted in exons 12 and 15 of the HMBS gene. Sequencing revealed different mu tations in each patient: a two-base deletion of CT at nucleotide 730-731 (7 30delCT), and also a two-base deletion of CA at position 982-983 (982delCA) . Both of the deletion mutations lead to truncated proteins with an abnorma l C-terminus, which would be expected to decrease the stability and/or acti vity of HMBS. Using the cleavage assays, we were able to definitively ident ify gene carriers in the family. This study adds a novel mutation to those that have been previously reported, and emphasizes that molecular analysis would be very useful not only for the identification of asymptomatic gene c arriers in the family but also for the detection of ancestral founders in p orphyria families.