title: Dominant negative allele (N47D) in a compound heterozygote for a variant of 6-pyruvoyltetrahydropterin synthase deficiency causing transient hyperphenylalaninemia.
abstract: Mutations in the 6-pyruvoyltetrahydropterin synthase (PTPS) gene result in persistent hyperphenylalaninemia and severe catecholamine and serotonin deficiencies. We investigated at the DNA level a family with a PTPS-deficient child presenting with an unusual form of transient hyperphenylalaninemia. The patient exhibited compound heterozygosity for the PTPS-mutant alleles N47D and D116G. Transfection studies with single PTPS alleles in COS-1 cells showed that the N47D allele was inactive, while D116G had around 66% of the wild-type activity. Upon co-transfection of two PTPS alleles into COS-1 cells, the N47D allele had a dominant negative effect on both the wild-type PTPS and the D116G mutant with relative reduction to about 20% of control values. Whereas the mother and the father had reduced enzyme activity in red blood cells (34.7% and 51.7%, respectively) and skin fibroblasts (2.8% and 15.4%, respectively), the clinically normal patient had in these cells activities at the detection limits, although PTPS-cross-reactive material was present in the fibroblasts. The specifically low PTPS activity in the mother's cells corroborated the evidence of a dominant negative effect of the maternal N47D allele on wild-type PTPS.
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Scherer-Oppliger
authors.forename: A
authors.initials: A
authors.lastname: Matasovic
authors.forename: S
authors.initials: S
authors.lastname: Laufs
authors.forename: H L
authors.initials: HL
authors.lastname: Levy
authors.forename: E J
authors.initials: EJ
authors.lastname: Quackenbush
authors.forename: N
authors.initials: N
authors.lastname: Blau
authors.forename: B
authors.initials: B
authors.lastname: Thöny
mesh_terms: D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D008297:Male; D010649:Phenylalanine / Q000097:blood*; D019761:Phosphorus-Oxygen Lyases / Q000097:blood / Q000172:deficiency*; D016133:Polymerase Chain Reaction; D014162:Transfection
chemical_list: D010649:Phenylalanine; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase