Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute intermittent porphyria (AIP) is an autosomally dominant inherited metabolic disorders caused by decreased activity of porphobilinogen deaminase, the third enzyme in the human heme biosynthetic pathway. We report here the first mutations in the human porphobilinogen deaminase gene in seven unrelated patients from the Czech and Slovak Republics with acute intermittent porphyria. We used denaturing gradient gel electrophoresis to screen all 15 exons and exon/intron boundaries of the porphobilinogen deaminase gene. Polymerase chain reaction products of abnormal migration patterns were subjected to direct sequencing to identify the causative mutations. Thus we revealed four novel mutations and three which have been previously described. Of the four novel mutations, two were mis-sense (G24S, V267M), one was a single base insertion (158insA) that produced a stop codon 12 codons downstream, and one was a single base substitution in intron 12 (771 + 1) resulting in a splicing defect. The three previously detected mutations were mis-sense mutations (R26C, R26H, G111R). These results suggest a high allelic heterogeneity in Czech and Slovak patients.
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PMID:Molecular analysis of porphobilinogen (PBG) deaminase gene mutations in acute intermittent porphyria: first study in patients of Slavic origin. 923 57

In this study, we report a large Finnish family in which an Alu element interferes with the coding region of the porphobilinogen deaminase (PBGD) gene resulting in acute intermittent porphyria (AIP). Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis of exon 5 among patients showed an abnormal band around 350 bp apart from the normal bands. Subcloning and sequencing of the fragment revealed a 333-bp Alu sequence that was directly inserted into exon 5 in antisense orientation. The junction sequences included a 13-bp target site duplication. This Alu cassette belongs to a Ya5 subfamily, one of the youngest and currently most active Alu subfamilies in evolution. The Alu insertion resulted in a dramatically decreased steady-state level of the allelic transcript, as this Alu sequence could not be demonstrated by direct sequencing of the amplified cDNA synthesized from total RNA extracted from the patients' lymphoblast cell lines. A stop codon present in the reading frame causes premature termination of PBGD synthesis. The predicted polypeptide contains 64 of the 361 amino acids of PBGD, followed by 13 amino acids that are not identical to the PBGD polypeptide. To further characterize the consequences of the insertion, the Alu sequence was inserted into exon 5 of the PBGD cDNA and expressed in the eukaryotic COS-1 cell line. The mutated construct expressed no enzyme activity comparable to that of the wild-type PBGD; furthermore, no mutant protein could be detected by Western blot analysis.
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PMID:Insertion of Alu element responsible for acute intermittent porphyria. 1040 72