[Molecular genetic study of acute intermittent porphyria in Russia: mutation analysis and functional polymorphism search in porphobilinogen deaminase gene].
Acute intermittent porphyria (AIP) is an autosomal dominant hereditary disease, caused by partial deficiency of porphobilinogen deaminase (PBGD), one of the key enzymes ofheme biosynthesis. This study describes molecular genetics of AIP in Russia. Mutation analysis of PBGD gene in 70 unrelated patients revealed 47 various genetic defects, 28 of which had not been described previously. Mutations 53delT and Argl 73 Trp (recorded 8 times, in total 23%) proved to be the most common in Russia. Microdeletion 53delThas monophyletic origin and was found only in Russia. Molecular genetic examination of 132 relatives of AIP patients from 40 families revealed 52 latent carriers of the disease. Low (about 10%) AIP penetrance indicates that a mutation in the PBGD gene is an important but not sufficient prerequisite for clinical manifestation of the disease. Modulation of penetrance in erythropoietic protoporphyria by coinheritance of a mutant allele and a functionally defective wild type allele of ferrochetalase gene has been shown previously. We hypothesized that similar mechanism works in AIP. Sequencing of the full length PBGD genes from unrelated AIP patients as well as SN P analysis, and the analysis of abnormal PBGD mRNA splicing showed that in case ofAIP, this hypothesis is not true and some other factors are responsible for the penetrance of this disease.
V L
VL
Surin
Iu A
IuA
Luchinina
D S
DS
Selivanova
Ia S
IaS
Pustovoĭt
I S
IS
Karpova
A V
AV
Pivnik
A V
AV
Luk'ianenko
S K
SK
Kravchenko
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005294:Ferrochelatase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D008297:Male; D009154:Mutation; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D017118:Porphyria, Acute Intermittent / Q000201:enzymology / Q000235:genetics*; D012426:Russia
D011163:Hydroxymethylbilane Synthase; D005294:Ferrochelatase