Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Lopes Marques, M (Author) Other; Pacheco, AR (Author) Other; Peixoto, MJ (Author) Other; Cardoso, AR (Author) Other; Serrano, C (Author) Other; Amorim, A (Author) FCUP; Prata, MJ (Author) FCUP; Cooper, DN (Author) Other; Luisa Azevedo (Author) FCUP

Journal

Title: Human Mutation

Vol. 42

Pages: 978-989

ISSN: 1059-7794

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 2 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00T-Y0X

DOI: 10.1002/humu.24221

Abstract (EN): Understanding the role of common polymorphisms in modulating the clinical phenotype when they co-occur with a disease-causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild-type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild-type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis-interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12