title: Manifestation of hawkinsinuria in a patient compound heterozygous for hawkinsinuria and tyrosinemia III.
abstract: Mutations in the gene for 4-hydroxyphenylpyruvic acid dioxygenase (HPD) cause either autosomal recessive tyrosinemia type III or autosomal dominant hawkinsinuria. We report a 6-month-old Indian infant who is compound heterozygous for both alleles and who has hawkinsinuria but not tyrosinemia type III based on biochemical investigations. The HPD gene was directly sequenced in the proband and both parents. The mechanistic model of the enzymatic function was built using the known structure of rat HPD. We identified a novel hawkinsinuria mutation, Asn241Ser, and a known tyrosinemia type III mutation, Ile335Met, in trans configuration. The structural analysis of the active site revealed that the IIe335Met mutation is situated in the close vicinity of one of the two highly conserved Phe rings which stack with the phenol ring of the substrate. The Asn241Ser mutation is situated further away from the 4-hydroxyphenylpyruvate binding pocket. Assuming that Asn241Ser causes hawkinsinuria, we propose positioning the dioxygen molecule in the HPD-catalyzed reaction as a novel role for the Asn residue. The IIe335Met allele is equivalent to a null mutation while the Asn241Ser allele results in a partially active enzyme with an uncoupled turnover causing hawkinsinuria.
authors.affiliation: Division of Biochemical and Paediatric Genetics, University Children's Hospital, Währinger Gürtel 18-20, A-1090 Vienna, Austria. bellarmine.item@meduniwien.ac.at
authors.forename: Chike Bellarmine
authors.initials: CB
authors.lastname: Item
authors.forename: Ivana
authors.initials: I
authors.lastname: Mihalek
authors.forename: Oliver
authors.initials: O
authors.lastname: Lichtarge
authors.forename: Anil
authors.initials: A
authors.lastname: Jalan
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.forename: Adolf
authors.initials: A
authors.lastname: Muhl
authors.forename: Olaf A
authors.initials: OA
authors.lastname: Bodamer
mesh_terms: D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000172:deficiency / Q000235:genetics*; D000603:Amino Acids, Sulfur / Q000652:urine*; D053138:Cyclohexenes / Q000652:urine*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D006580:Genetic Carrier Screening; D006801:Humans; D007223:Infant; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D020176:Tyrosinemias / Q000235:genetics* / Q000652:urine*
chemical_list: D000603:Amino Acids, Sulfur; D053138:Cyclohexenes; C014578:hawkinsin; D004247:DNA; D015111:4-Hydroxyphenylpyruvate Dioxygenase