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Dominant negative allele (N47D) in a compound heterozygote for a variant of 6‐pyruvoyltetrahydropterin synthase deficiency causing transient hyperphenylalaninemia
Author(s) -
SchererOppliger Tanja,
Matasovic Ana,
Laufs Stephanie,
Levy Harvey L.,
Quackenbush Elisabeth J.,
Blau Nenad,
Thöny Beat
Publication year - 1999
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1999)13:4<286::aid-humu4>3.0.co;2-c
Subject(s) - hyperphenylalaninemia , biology , heterozygote advantage , compound heterozygosity , allele , genetics , gene , phenylalanine , amino acid
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. Hum Mutat 13:286–289, 1999. © 1999 Wiley‐Liss, Inc.