Dominant negative allele (N47D) in a compound heterozygote for a variant of 6-pyruvoyltetrahydropterin synthase deficiency causing transient hyperphenylalaninemia.
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Scherer-Oppliger T, Matasovic A, Laufs S, Levy HL, Quackenbush EJ, Blau N, Thony B
Dominant negative allele (N47D) in a compound heterozygote for a variant of 6-pyruvoyltetrahydropterin synthase deficiency causing transient hyperphenylalaninemia.
Hum Mutat. 1999;13(4):286-9.
- PubMed ID
- 10220141 [ View in PubMed]
- 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.