Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Acute intermittent porphyria (AIP) is a very rare autosomal dominant disorder with low penetrance. Mutations in the gene of the porphobilinogen deaminase (PBG-D), also called hydroxymethylbilane synthase (HMBS), cause a partial deficiency of this enzyme of the heme biosynthetic pathway. Overstimulation of heme biosynthesis causes clinical symptoms. Because of the variability of the symptoms, diagnosis is often delayed. Using two approaches for genetic analysis, first in a stepwise manner, then sequencing extensive parts of the gene, the screening of the DNA of 20 unrelated individuals revealed 20 different mutations, 11 of which had not been reported previously. The novel mutations affected intron 1 (33 + 2 T-->C), exon 5 (181 G-->C), intron 6 (267-61 del 8 bp), intron 7 (345-1 G-->C), intron 9 (498 + 15 G-->T and 499-13 Delta-14 bp indel TGA), intron 13 (825 + 1 G-->C and 825 + 2 T-->C), exon 15 (962 G-A, 1067 del A and 1067-1068 ins 5 bp). The other nine mutations detected affected intron 14, exons 6, 7, 8, 9, 10 (3x) and 12. In the majority of AIP patients, the genotype does not predict phenotypic expression. Since the sudden manifestation of the disease maybe prevented by early diagnosis, identification of AIP gene carriers is the best preventive measure. This was performed in five families, revealing 10 additional AIP gene carriers.
Blood Cells Mol Dis
PMID:Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations. 1500 23

Acute intermittent porphyria (AIP), an inborn error of metabolism, results from the deficient activity of the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD). Clinical symptoms of this autosomal dominant hepatic porphyria include episodic acute attacks of abdominal pain, neuropathy, and psychiatric disturbances. Current therapy based on intravenous heme administration is palliative and there is no way to prevent the attacks. Thus, efforts are focused on methods to replace the deficient activity in the liver to prevent the acute attacks of this hepatic porphyria. Here we explore the efficiency of a non-viral gene delivery to obtain PBGD expression in the liver of AIP transgenic mice. Four vectors were evaluated: naked DNA and DNA complexed to liposomes, polyethylenimine (PEI), and PEI-galactose, using a luciferase construct as reporter gene. The vectors were administered intravenously or directly into the portal vein with transient blood flow blockage. After tail vein injection of the DNA complexes, the liposome vector had the highest luciferase expression in lung and less in liver. When injected into the portal vein, the naked DNA had considerably higher hepatic reporter gene expression; 100 microg of naked DNA had the highest hepatic luciferase expression 24h after portal vein injection. When these vectors were used to deliver the PBGD gene into the AIP mouse model no enhancement of the endogenous PBGD activity in liver was detectable, despite the presence of the PBGD-plasmids as verified by PCR. Thus, more efficient non-viral vectors are needed to express sufficient PBGD activity over the endogenous hepatic level (approximately 30% of normal) in this murine system.
Mol Genet Metab 2004 May
PMID:Non-viral delivery of the porphobilinogen deaminase cDNA into a mouse model of acute intermittent porphyria. 1511 Mar 17

Acute intermittent porphyria (AIP) is a genetic disorder caused by a deficiency of porphobilinogen deaminase (PBGD), the 3rd enzyme in heme synthesis. It is clinically characterized by acute attacks of neuropsychiatric symptoms and biochemically by increased urinary excretion of the porphyrin precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA). A mouse model that is partially deficient in PBGD and biochemically mimics AIP after induction of the hepatic ALA synthase by phenobarbital was used in this study to identify the site of formation of the presumably toxic porphyrin precursors and study the effect of enzyme-replacement therapy by using recombinant human PBGD (rhPBGD). After 4 d of phenobarbital administration, high levels of PBG and ALA were found in liver, kidney, plasma, and urine of the PBGD-deficient mice. The administration of rhPBGD intravenously or subcutaneously after a 4-d phenobarbital induction was shown to lower the PBG level in plasma in a dose-dependent manner with maximal effect seen after 30 min and 2 h, respectively. Injection of rhPBGD subcutaneously twice daily during a 4-d phenobarbital induction reduced urinary PBG excretion to 25% of the levels found in PBGD-deficient mice administered with only phenobarbital. This study points to the liver as the main producer of PBG and ALA in the phenobarbital-induced PBGD-deficient mice and demonstrates efficient removal of accumulated PBG in plasma and urine by enzyme-replacement therapy.
Mol Med
PMID:Biochemical characterization of porphobilinogen deaminase-deficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement. 1520 40

The aim of this study was to investigate the potential of gene therapy in the treatment of acute intermittent porphyria (AIP), a disorder caused by a partial deficiency of porphobilinogen deaminase (PBGD), the third enzyme in heme synthesis. The condition is biochemically characterized by accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here we present the first experiments in vivo using adenoviral vectors to replace the deficient enzyme in the liver of an AIP mouse model. The use of adenoviral vector carrying the cDNA of luciferase in wild-type mice confirmed that transgene expression after intravenous administration was found mainly in liver. When PBGD-deficient mice were administered with adenoviral vector carrying the cDNA of mouse PBGD, the hepatic PBGD activity increased in a dose- and time-dependent manner. The highest activity was found 7 days after injection and remained high after 29 days. The expressed enzyme was shown to correct the metabolic defect in the PBGD-deficient mice as no accumulation of ALA or PBG occurred in plasma, liver, or kidney after induction of heme synthesis by phenobarbital. The study demonstrates that hepatic PBGD expression prevents the accumulation of porphyrin precursors, suggesting a future potential for gene therapy in AIP.
Mol Ther 2004 Aug
PMID:Adenoviral-mediated expression of porphobilinogen deaminase in liver restores the metabolic defect in a mouse model of acute intermittent porphyria. 1529 80

The polycomb group protein enhancer of zeste 2 (EZH2) is a transcriptional repressor involved in the control of cellular proliferation and oncogenesis. The aim of the present study was to quantify EZH2 expression in bladder carcinomas and to correlate the data with clinicopathological findings. EZH2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction in tumor tissue specimens obtained from 37 patients with urothelial carcinomas of the bladder and in four bladder cancer cell lines. EZH2 levels were normalized to expression of the housekeeping porphobilinogen deaminase gene. EZH2 transcripts were commonly detected in tumor tissue. Transcript levels correlated significantly with the invasiveness of bladder tumors (p = 0.029) with elevated EZH2 mRNA expression measured in invasive bladder carcinomas (median value, 38.92) compared with non-invasive tumors (15.51). In addition, levels of expression were significantly higher in high-grade (G3) than in low-grade (G1/2) lesions (p < 0.001). EZH2 mRNA levels in bladder carcinoma cell lines were within the range of high-grade invasive bladder cancers. In conclusion, expression levels of EZH2 are elevated in aggressive and invasive urothelial carcinomas, suggesting that deregulated EZH2 expression may be involved in the progression of bladder tumors.
Int J Mol Med 2005 Aug
PMID:Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. 1601 74

Heme biosynthesis represents one of the most essential metabolic pathways in living organisms, providing the precursors for cytochrome prosthetic groups, photosynthetic pigments, and vitamin B(12). Using genomic data, we have compared the heme pathway in the diatom Thalassiosira pseudonana and the red alga Cyanidioschyzon merolae to those of green algae and higher plants, as well as to those of heterotrophic eukaryotes (fungi, apicomplexans, and animals). Phylogenetic analyses showed the mosaic character of this pathway in photosynthetic eukaryotes. Although most of the algal and plant enzymes showed the expected plastid (cyanobacterial) origin, at least one of them (porphobilinogen deaminase) appears to have a mitochondrial (alpha-proteobacterial) origin. Another enzyme, glutamyl-tRNA synthase, obviously originated in the eukaryotic nucleus. Because all the plastid-targeted sequences consistently form a well-supported cluster, this suggests that genes were either transferred from the primary endosymbiont (cyanobacteria) to the primary host nucleus shortly after the primary endosymbiotic event or replaced with genes from other sources at an equally early time, i.e., before the formation of three primary plastid lineages. The one striking exception to this pattern is ferrochelatase, the enzyme catalyzing the first committed step to heme and bilin pigments. In this case, two red algal sequences do not cluster either with the other plastid sequences or with cyanobacterial sequences and appear to have a proteobacterial origin like that of the apicomplexan parasites Plasmodium and Toxoplasma. Although the heterokonts also acquired their plastid via secondary endosymbiosis from a red alga, the diatom has a typical plastid-cyanobacterial ferrochelatase. We have not found any remnants of the plastidlike heme pathway in the nonphotosynthetic heterokonts Phytophthora ramorum and Phytophthora sojae.
Mol Biol Evol 2005 Dec
PMID:Mosaic origin of the heme biosynthesis pathway in photosynthetic eukaryotes. 1609 70

Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the gene coding for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. So far, more than 242 different mutations responsible for AIP have been identified in this gene. In an Italian family with typical clinical and biochemical signs of AIP, no mutation was found by direct sequencing of the entire hydroxymethylbilane synthase gene (HMBS). All the symptomatic patients showed apparent homozygosity and absence of mendelian segregation for eleven common polymorphisms along the gene. Excluding interference of polymorphisms in the primer sites, we assumed the presence of a complete HMBS gene deletion. In order to identify the size of this deletion, single nucleotide polymorphisms (SNPs) analysis was extended to flanking genes, H2A Histone Family member X (H2AFX) and Dolichyl-Phosphate N-Acetylglucosamine Phosphotransferase 1 (DPAGT1), downstream and Vacuolar protein sorting 11 (VPS11), upstream. Heterozygous polymorphisms in the VPS11 and DPAGT1 genes were found. Thus, we performed a Long-PCR with primers situated in regions outside the homozygous polymorphisms and we identified a double deletion with inversion on chromosome 11 (g22516974_22524062del7088, g22524062_22524278inv216, g22524278_22531093del6815). Even if the deletions include the entire HMBS and H2AFX genes and 1463 bp of the final portion of DPAGT1 gene, our patients had no other symptoms than AIP.
Blood Cells Mol Dis
PMID:A large deletion on chromosome 11 in acute intermittent porphyria. 1682 19

Acute intermittent porphyria is an inherited disease of haem biosynthesis that results from mutation of the gene for the enzyme porphobilinogen deaminase. Many different mutations have been located throughout the gene. The three-dimensional structure of the enzyme helps in understanding how these mutations lead to inactivation even when, in some cases, the mutated product is abundant and folded correctly.
Mol Med Today 1995 Aug
PMID:Molecular basis of acute intermittent porphyria. 1760 85

Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis caused by molecular defects in the hydroxymethylbilane synthase (HMBS) gene. In this study, we report two novel missense sequence variations in the HMBS gene, T59I (C176T) and V215M (G643A), in two patients with clinical symptoms compatible with acute attacks of porphyria. However, only the patient who carried V215M presented with full AIP-affirming biochemical evidence. Both variant proteins were expressed in a prokaryotic system and characterized in vitro. Recombinant T59I and V215M had residual activity of 80.6% and 19.4%, respectively, of that of the wild type enzyme. Moreover, changes in K(m), V(max) and thermostability observed in the recombinant V215M suggest a causal relationship between V215M and AIP. The association between the T59I substitution and AIP is less obvious. Based on our investigation, substitution T59I is more likely to be a mutation with a weak effect than a rare form of polymorphism. This study demonstrates that in vitro characterization of missense variations in the HMBS gene can provide valuable information for the interpretation of clinical, biochemical and genetic data, for establishing a diagnosis of AIP. It also highlights the fact that there are still many aspects to be investigated concerning AIP and corroborates the need to report new data that can help to clarify the genotype-phenotype relationship.
Mol Genet Metab 2008 Jul
PMID:Characterization of two missense variants in the hydroxymethylbilane synthase gene in the Israeli population, which differ in their associations with acute intermittent porphyria. 1840 50

During development, human beta-globin locus regulation undergoes two critical switches, the embryonic-to-fetal and fetal-to-adult hemoglobin switches. To define the role of the fetal (A)gamma-globin promoter in switching, human beta-globin-YAC transgenic mice were produced with the (A)gamma-globin promoter replaced by the erythroid porphobilinogen deaminase (PBGD) promoter (PBGD(A)gamma-YAC). Activation of the stage-independent PBGD(A)gamma-globin strikingly stimulated native (G)gamma-globin expression at the fetal and adult stages, identifying a fetal gene pair or bigenic cooperative mechanism. This impaired fetal silencing severely suppressed both delta- and beta-globin expression in PBGD(A)gamma-YAC mice from fetal to neonatal stages and altered kinetics and delayed switching of adult beta-globin. This regulation evokes the two human globin switching patterns in the mouse. Both patterns of DNA demethylation and chromatin immunoprecipitation analysis correlated with gene activation and open chromatin. Locus control region (LCR) interactions detected by chromosome conformation capture revealed distinct spatial fetal and adult LCR bigenic subdomains. Since both intact fetal promoters are critical regulators of fetal silencing at the adult stage, we concluded that fetal genes are controlled as a bigenic subdomain rather than a gene-autonomous mechanism. Our study also provides evidence for LCR complex interaction with spatial fetal or adult bigenic functional subdomains as a niche for transcriptional activation and hemoglobin switching.
Mol Cell Biol 2009 Mar
PMID:Evidence for a bigenic chromatin subdomain in regulation of the fetal-to-adult hemoglobin switch. 1911 59


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