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

Lopes-Marques, Mónica, Pacheco, Ana Rita, Peixoto, Maria João, Cardoso, Ana Rita, Serrano, Catarina, Amorim, António, Prata, Maria João, Cooper, David N. ORCID: https://orcid.org/0000-0002-8943-8484 and Azevedo, Luísa 2021. Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity. Human Mutation 42 (8) , pp. 978-989. 10.1002/humu.24221

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License
Publisher:	Wiley
ISSN:	1059-7794
Date of First Compliant Deposit:	8 June 2021
Date of Acceptance:	18 May 2021
Last Modified:	05 May 2023 02:07
URI:	https://orca.cardiff.ac.uk/id/eprint/141791

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