title: Molecular study of the hydroxymethylbilane synthase gene (HMBS) among Polish patients with acute intermittent porphyria.
abstract: 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.
authors.affiliation: Porphyria center, Institute of Hematology and Blood Transfusion, Warsaw, Poland.
authors.forename: Anita
authors.initials: A
authors.lastname: Gregor
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Schneider-Yin
authors.forename: Urszula
authors.initials: U
authors.lastname: Szlendak
authors.forename: Albert
authors.initials: A
authors.lastname: Wettstein
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lipniacka
authors.forename: Urszula B
authors.initials: UB
authors.lastname: Rüfenacht
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Minder
mesh_terms: D000328:Adult; D000622:Aminolevulinic Acid / Q000652:urine; D004796:Clinical Enzyme Tests / Q000379:methods / Q000592:standards; D004247:DNA / Q000235:genetics; D005260:Female; D005821:Genetic Techniques / Q000592:standards; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D011044:Poland; D017118:Porphyria, Acute Intermittent / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*
chemical_list: D000622:Aminolevulinic Acid; D004247:DNA; D011163:Hydroxymethylbilane Synthase