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1.
Genetika ; 46(4): 540-52, 2010 Apr.
Article in Russian | MEDLINE | ID: mdl-20536026

ABSTRACT

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.


Subject(s)
Ferrochelatase/genetics , Hydroxymethylbilane Synthase/genetics , Mutation , Polymorphism, Single Nucleotide , Porphyria, Acute Intermittent/genetics , Alleles , Alternative Splicing/genetics , DNA Mutational Analysis/methods , Female , Ferrochelatase/metabolism , Humans , Male , Penetrance , Porphyria, Acute Intermittent/enzymology , Russia
2.
Ter Arkh ; 79(8): 52-6, 2007.
Article in Russian | MEDLINE | ID: mdl-17926472

ABSTRACT

AIM: To analyse manifestations and experience in primary screening diagnosis of acute porphyrias which are rarely encountered and little known by general practitioners. MATERIAL AND METHODS: The data on 100 patients with the diagnosis acute porphyria have been analysed. Porphyrin metabolism in differential diagnosis was estimated according to standard techniques. RESULTS: Analysis of primary diagnosis of acute porphyria hepatica in Russia (region-related prevalence, duration of diagnosis, complications because of late pathogenetic treatment) demonstrates the importance of screening diagnosis of acute porphyria at the level of municipal clinics. CONCLUSION: Early diagnosis prevents severe complications of acute porphyria and reduces cost of examinations in search of accurate diagnosis.


Subject(s)
Mass Screening/methods , Porphyria, Acute Intermittent/diagnosis , Adolescent , Adult , Aminolevulinic Acid/metabolism , Diagnosis, Differential , Female , Humans , Hydroxymethylbilane Synthase/metabolism , Male , Middle Aged , Porphobilinogen/metabolism , Porphyria, Acute Intermittent/metabolism , Porphyrins/blood , Retrospective Studies , Russia , Spectrophotometry
3.
Genetika ; 43(6): 831-40, 2007 Jun.
Article in Russian | MEDLINE | ID: mdl-17853810

ABSTRACT

In search of new efficient markers for genetic diagnostics of hemophilia A, two tri-nucleotide microsatellite repeats (STR) at chromosome X loci, which flank coagulation factor VIII gene (F8), namely STR HA472--CTT-repeat, which is localized adjacent to the GAB3 gene 163 bp apart from the 3' end of the F8 gene and STR HA544--repeat (CTT)x(ATT)y located at a distance of 375 bp from the 5' end of the F8 gene were discovered. Detailed analysis using PCR and sequencing has shown that STR HA472 contains two long variable CTT-blocks separated by small spacer CCTCCC. The location of recognition site of restriction endonuclease Mnl1 (CCTC) in the spacer permits to test differentially the polymorphic blocks and thus to increase the analysis informativity. STR HA544 is also represented by two polymorphic blocks (CTT and ATT), for separate amplification of which highly informative PCR amplification assays were elaborated. The study has been done using DNA samples of 212 individuals (125 women) from 48 families with hemophilia A carriers. Our results point to Mendelian inheritance of the markers studied, a high number of allelic variants and high heterozygosity, which was 90% and 100% for HA544 and HA472, respectively. This permitted us to use these data for practical gene diagnostics of the carriers and prenatal diagnostics of hemophilia A. In addition to high informativity STR HA472 and HA544 are highly important for diagnostics as they are located at a shorter distance than other known extragenic polymorphisms of the F8 gene. In contrast to dinucleotide repeats, trinucleotide repeats are readily tested, not requiring high-resolution electrophoretic systems. In addition, they are located on the opposite sites of the F8 gene. This permits to control homologous recombination events in the locus and thus to prevent diagnostic mistakes.


Subject(s)
Factor VIII/genetics , Genetic Markers , Hemophilia A/genetics , Microsatellite Repeats , Base Sequence , Chromosomes, Human, X/genetics , Female , Genetic Carrier Screening , Hemophilia A/diagnosis , Humans , Male , Molecular Sequence Data , Pedigree
4.
Genetika ; 43(4): 560-6, 2007 Apr.
Article in Russian | MEDLINE | ID: mdl-17555134

ABSTRACT

Frequencies of the CIT SNP alleles at position 2403 of the human coagulation factor VIII gene intron 1, containing the AluI restriction endonuclease recognition site, were examined. Genomic DNA samples for the analysis were obtained from the consulted women and their relatives from the families with hemophilia A. A total of 221 unrelated X chromosomes were studied. The two allelic variants were found with similar frequencies of T(Alu+), 0.53 and C(Alu-), 0.47. The heterozygosity index evaluated as equal to 0.50 was correlated with the experimental heterozygote number. The absence of a tight linkage between the AluI SNP and the widely used in the hemophilia A gene diagnostics HindIII polymorphism (CIT SNP at position 103 of intron 19) was demonstrated. Summarized informativity of these two markers for obligate carriers and for those detected in this study constituted 68% (32 out of 47). At the same time using one of the markers, only 40% (HindIII) and 51% (AluI) of the consulted women were informative. The new marker was used in 13 prenatal DNA diagnostics of hemophilia A. A new deletion polymorphism (del TGA, position 2281-2283 of intron 1) was described in close proximity of the AluI SNP with the frequency of about 0.05. among the five other SNP of the factor VIII gene examined (Bme 18I, intron 1; HpaII, intron 13; MnlI, exon 14; Bst4CI, exon 25; and MseI, exon 26) no effective diagnostic markers were found. Only the MnlI polymorphism could be recommended for limited usage.


Subject(s)
Alu Elements/genetics , Chromosomes, Human, X/genetics , Factor VIII/genetics , Hemophilia A/genetics , Introns/genetics , Polymorphism, Single Nucleotide , Alleles , Female , Gene Frequency , Genetic Linkage , Genetic Markers , Hemophilia A/diagnosis , Humans , Male , Pregnancy , Prenatal Diagnosis
5.
Ter Arkh ; 75(7): 68-73, 2003.
Article in Russian | MEDLINE | ID: mdl-12934485

ABSTRACT

AIM: To characterize patients with various nosological unities [symbol: see text] of porphyria in accordance with their age, clinical symptoms, provoking factors, therapy and outcome. MATERIAL AND METHODS: Patients with acute intermittent porphyria (43), hereditary coproporphyria (8), variegate porphyria (3), porphyria cutanea tarda (7), hepatoerythropoietic porphyria (1), and hereditary erythropoietic porphyria (2) were studied. One patient was suspected of porphyria caused by deficiency of delta-aminolevulenic acid dehydrogenase. RESULTS: The patients were from the CIS. The overwhelming majority of them were young and middle-aged subjects. Rapid development of the disease and severe neurological symptoms were predominantly observed in patients with acute forms of porphyria. CONCLUSION: Early diagnosis of porphyrin metabolism disorders makes it possible to decrease abruptly the number of cases leading to severe complications, disability, and fatal outcome. The use of inexpensive methods of screening of porphyrin metabolism disorders provides a promising approach to solving this problem. These methods should be used in municipal hospitals. In addition, asymptomatic carriers of defective gene should be revealed at the preclinical stage using various methods of molecular genetic assay.


Subject(s)
Porphyrias/diagnosis , Porphyrins/metabolism , Acute Disease , Adolescent , Adult , Arginine/therapeutic use , Chronic Disease , Female , Heme/therapeutic use , Humans , Inosine Diphosphate/therapeutic use , Middle Aged , Octreotide/therapeutic use , Plasmapheresis , Porphyria, Acute Intermittent/diagnosis , Porphyria, Acute Intermittent/drug therapy , Porphyria, Acute Intermittent/etiology , Porphyria, Acute Intermittent/metabolism , Porphyria, Erythropoietic/diagnosis , Porphyria, Erythropoietic/drug therapy , Porphyria, Erythropoietic/etiology , Porphyria, Erythropoietic/metabolism , Porphyrias/drug therapy , Porphyrias/etiology , Porphyrias/metabolism
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