Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2010, vol. 19, nr 4, July-August, p. 497–501

Publication type: original article

Language: English

New Mutations of Porphobilinogen Deaminase Gene in Polish Families with Acute Intermittent Porphyria

Nowe mutacje genu deaminazy porfobilinogenu w polskich rodzinach z ostrą przerywaną porfirią

Urszula Szlendak1,, Jolanta Bianketti2,, Anita Gregor1,, Ksenia Bykowska3,

1 Laboratory of Porphyria, Department of Hematological Diagnostics and Transfusiology, Institute of Hematology and Blood Transfusion, Warsaw, Poland

2 Outpatient Clinic for Porphyria Patients and Relatives, Institute of Hematology and Blood Transfusion, Warsaw, Poland

3 Von Willebrand Disease Laboratory, Institute of Hematology and Blood Transfusion, Warsaw, Poland

Abstract

Background. Acute intermittent porphyria (AIP) is an autosomal dominantly inherited disorder of low clinical penetrance. A 50% lower activity of porphobilinogen deaminase (PBGD) stands for the metabolic error in AIP. The PBGD gene is composed of 15 exons of 39–438 bp in length and it is mapped to 11q24.1–24.2 chromosome. So far over 300 various mutations of the PBGD gene responsible for AIP have been described.
Objectives. Description of molecular background of AIP in patients from Polish population diagnosed based on biochemical analyses. Molecular diagnosis of AIP in family members.
Material and Methods. Biochemical study, such as porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) excretion with urine and PBGD activity in erythrocyres have been examined in all probands and family members. AIP patients and their family members underwent further molecular diagnosis.
Results. Among 16 families with AIP diagnosis made on biochemical tests 10 new PBGD gene mutations have been discovered not yet described. Missense (83G>T, 89T>G, 281T>G, 293A>C, 500G>C and 796G>C); and frameshift (470delT, 716-725delACGATCCCGA, 723-724insCC and 969delT) mutation types have been revealed.
Conclusion. Similar to other populations, 10 new mutations revealed in Polish population can suggest heterogeneity of mutatios responsible for AIP. Biochemical methods can sometimes fail to diagnose the disease. Molecular analysis is much more reliable method to diagnose AIP in asymptomatic members of probands.

Streszczenie

Wprowadzenie. Ostra przerywana porfiria (AIP) jest chorobą uwarunkowaną genetycznie, dziedziczoną w sposób autosomalny dominujący o niskiej penetracji klinicznej. Błędem metabolicznym w AIP jest obniżona ok. 50% aktywność deaminazy porfobilinogenu (PBGD). Gen PBGD jest zbudowany z 15 eksonów o długości 39–438 bp i umiejscowiony na chromosomie 11q24.1–24.2. Dotychczas na świecie opisano ponad 300 różnych mutacji genu PBGD odpowiedzialnych za AIP.
Cel pracy. Poznanie podłoża molekularnego odpowiedzialnego za AIP w populacji polskiej u pacjentów, u których rozpoznano porfirię na podstawie badań biochemicznych. Diagnostyka molekularna członków rodzin z AIP.
Materiał i metody. U wszystkich probandów i członków ich rodzin wykonano badania biochemiczne: wydalanie porfobilinogenu (PBG) i kwasu δ-aminolewulinowego (ALA) w moczu oraz aktywność PBGD w erytrocytach. W celu dalszej diagnostyki rodzin z AIP u wszystkich pacjentów wykonano badanie DNA.
Wyniki. Wśród 16 polskich rodzin, u których rozpoznanie AIP postawiono na podstawie badań biochemicznych w genie PBGD stwierdzono 10 nowych mutacji nigdzie nieopublikowanych. Mutacje te to typu missens: 83G>T, 89T>G, 281T>G, 293A>C, 500G>C, 796G>C; typu frameshift: 470delT, 716-725delACGATCCCGA, 723- 724insCC, 969delT.
Wnioski. Stwierdzenie wśród 16 polskich rodzin 10 nowych mutacji w genie PBGD może świadczyć o heterogennej naturze mutacji odpowiedzialnych za AIP w populacji polskiej, podobnie jak w różnych krajach świata. Metody biochemiczne nie zawsze pozwalają jednoznacznie rozpoznać AIP. Analiza molekularna jest najdokładniejszą metodą pozwalającą na postawienie prawidłowego rozpoznania porfirii u bezobjawowych członków rodzin probandów.

Key words

acute intermittent porphyria, mutations

Słowa kluczowe

ostra przerywana porfiria, mutacje

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