Genes, Vol. 10, Pages 459: Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase

Genes, Vol. 10, Pages 459: Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase Genes doi: 10.3390/genes10060459 Authors: Martina Pecimonova Daniela Kluckova Frantisek Csicsay Kamila Reblova Jan Krahulec Dagmar Procházkova Ludovit Skultety Ludevit Kadasi Andrea Soltysova The molecular genetics of well-characterized inherited diseases, such as phenylketonuria (PKU) and hyperphenylalaninemia (HPA) predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene, is often complicated by the identification of many novel variants, often with no obvious impact on the associated disorder. To date, more than 1100 PAH variants have been identified of which a substantial portion have unknown clinical significance. In this work, we study the functionality of seven yet uncharacterized PAH missense variants p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, p.Ala342Pro, and p.Ile406Met first identified in the Czech PKU/HPA patients. From all tested variants, three of them, namely p.Asn167Tyr, p.Thr200Asn, and p.Ile406Met, exerted residual enzymatic activity in vitro similar to wild type (WT) PAH, however, when expressed in HepG2 cells, their protein level reached a maximum of 72.1% ± 4.9%, 11.2% ± 4.2%, and 36.6% ± 7.3% compared to WT PAH, respectively. Remaining variants were null with no enzyme activity and decreased protein levels in HepG2 cells. The chap...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Article Source Type: research