Molecular study of the hydroxymethlybilane 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.

Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias

“…Moreover, in all recently studied populations, hitherto unreported mutations continue to emerge. This continuing emergence of novel mutations despite the identification of more than 420 mutations, and the low de novo mutation rate demonstrates the usefulness of preliminary identification of the causative mutations in each newly-diagnosed family so that relatives with latent porphyria can be accurately identified (Donnelly et al 2002;Gregor et al 2002;Wiman et al 2002;Yasui et al 2002). Most mutations were restricted to a single family, and in accordance with the autosomic dominant inheritance, each patient had a single mutation restricted to one allele.…”

Nine mutations including three novel mutations among Russian patients with acute intermittent porphyria

“…The spectrum of mutations found in Russian AIP patients does not differ from that of western European populations. Six of the nine mutations characterized, c.77G>A (p.R26H), c.517C>T(p.R173W), c.583C>T(p.R195C), c.673C>T(p.R225X), c.739T>C(p.C247R), and c.748G>C(p.E250A), have been identified previously from several western European countries (Lee and Anvret, 1991;Llewellyn et al, 1993;Mgone et al, 1993;Lundin et al, 1995;Kauppinen et al, 1995), and two mutations, c.77G>A(p.R26H) and c.673C>T(p.R225X), from other eastern European countries (Rosipal et al, 1997;Gregor et al, 2002). Four additional mutations, c.53delT, c.202_203delCT, c.211-1G>C and c.344+2_344+5del, have previously been identified from other parts of Russian and Ukraine (Surin et al, 2001).…”

Nine novel mutations in the hydroxymethylbilane synthase gene of Polish patients with acute intermittent porphyria

“…As a main porphyria centre for Poland, we have so far registered 537 AIP patients from 328 families, yielding a prevalence of 1:70,000 inhabitants. Thus, the 11 cases described in this study together with 20 previously published cases account for only a fraction of all known AIP patients in Poland (6). Nevertheless, the small spectrum of mutations available so far does reflect a heterogeneous nature of the HMBS gene defects in the Polish AIP population, as in the cases of several other AIP populations (8, 10, 11).…”

“…To perform mutational analysis, EDTA-containing blood samples were collected from all individuals with informed consent. DNA isolation, PCR, mutation detection/confirmation by denaturing gradient gel electrophoresis (DGGE), sequencing and restriction enzyme analysis were carried out as previously described (6).…”