title: Hepatoerythropoietic Porphyria Caused by a Novel Homoallelic Mutation in Uroporphyrinogen Decarboxylase Gene in Egyptian Patients.
abstract: Porphyrias are metabolic disorders resulting from mutations in haem biosynthetic pathway genes. Hepatoerythropoietic porphyria (HEP) is a rare type of porphyria caused by the deficiency of the fifth enzyme (uroporphyrinogen decarboxylase, UROD) in this pathway. The defect in the enzymatic activity is due to biallelic mutations in the UROD gene. Currently, 109 UROD mutations are known. The human disease has an early onset, manifesting in infancy or early childhood with red urine, skin photosensitivity in sun-exposed areas, and hypertrichosis. Similar defects and links to photosensitivity and hepatopathy exist in several animal models, including zebrafish and mice. In the present study, we report a new mutation in the UROD gene in Egyptian patients with HEP. We show that the homozygous c.T163A missense mutation leads to a substitution of a conserved phenylalanine (amino acid 55) for isoleucine in the enzyme active site, causing a dramatic decrease in the enzyme activity (19 % of activity of wild-type enzyme). Inspection of the UROD crystal structure shows that Phe-55 contacts the substrate and is located in the loop that connects helices 2 and 3. Phe-55 is strictly conserved in both prokaryotic and eukaryotic UROD. The F55I substitution likely interferes with the enzyme-substrate interaction.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors.forename: M S
authors.initials: MS
authors.lastname: Farrag
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Mikula
authors.affiliation: University of Bordeaux, Bordeaux, France.
authors.forename: E
authors.initials: E
authors.lastname: Richard
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: V
authors.initials: V
authors.lastname: Saudek
authors.affiliation: University of Bordeaux, Bordeaux, France.
authors.forename: H
authors.initials: H
authors.lastname: De Verneuil
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Martásek
mesh_terms: D000293:Adolescent; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002921:Cicatrix / Q000150:complications; D004252:DNA Mutational Analysis; D004534:Egypt; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006983:Hypertrichosis / Q000150:complications; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D010375:Pedigree; D017121:Porphyria, Hepatoerythropoietic / Q000150:complications / Q000201:enzymology* / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D014575:Uroporphyrinogen Decarboxylase / Q000737:chemistry / Q000235:genetics*
chemical_list: D011993:Recombinant Fusion Proteins; D014575:Uroporphyrinogen Decarboxylase