Molecular study of the hydroxymethlybilane synthase gene (HMBS) among Polish patients with acute intermittent porphyria

✍ Scribed by Anita Gregor; Xiaoye Schneider-Yin; Urszula Szlendak; Albert Wettstein; Agnieszka Lipniacka; Urszula B. Rüfenacht; Elisabeth I. Minder

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 154 KB
• Volume: 19
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.9020

✦ Synopsis

Acute intermittent porphyria (AIP), an autosomal dominant disorder of heme biosynthesis, is due to mutations in hydroxymethylbilane synthase (HMBS; or porphobilinogen deaminase, PBGD) gene. In this study, we analyzed 20 Polish patients affected by AIP and we were able to characterize seven novel mutations. A nonsense mutation (Y46X), two frameshift mutations (315delT and 552delT) and a 131bp deletion (nucleotides 992-1123) give rise to truncated proteins. A donor splice site mutation IVS12+2T>C predicts skipping of exon 12. A missense mutation (D61Y) was identified in two apparently unrelated patients with a clearly clinical indication of AIP. An inframe 3-bp deletion (278-280delTTG) results in the removal of V93 from the enzyme. In addition to the novel mutations, nine previously described HMBS gene mutations -R26H, G111R, IVS7+1G>A, R149X, R173Q, 730-731delCT, R225X, 982-983delCA and G335D -were identified in this cohort. Our results demonstrate that molecular analysis of the PBGD gene is a more reliable method comparing to enzymatic assay in the diagnosis of AIP. Although more than 170 different mutations are known to the HMBS gene so far, over 40% of all mutations identified among the Polish AIP patients of this study are novel mutations, indicating the heterogeneity of molecular defects causing AIP.