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

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 cisinteractions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.

NAGS, CPS1, and SLC25A13 (Citrin) at the Crossroads of Arginine and Pyrimidines Metabolism in Tumor Cells

“…A high-throughput functional assay of all single nucleotide variant (SNV)-accessible amino acid replacements in human OTC revealed that around 5% of all OTC variants have up to 30% higher activity than wild-type human OTC [ 65 ]. Furthermore, human OTC with two common p.R46K and p.Q270R sequence variants had 40% higher enzymatic activity than the wild-type or either of the single mutant proteins [ 66 ]. Therefore, we hypothesize that some of the NAGS, CPS1, and citrin missense variants found in tumors can increase the activity of mutant proteins.…”

Characterization of a DRC1 null variant associated with primary ciliary dyskinesia and female infertility

“…One possibility is the fact that we have only analyzed the coding region, and thus we could not rule out the hypothesis of the existence of mutations in the non-coding regions of those genes being associated with this mRNA reduction. A previous work has shown that apparently neutral polymorphic variants can modulate the clinical phenotype [ 53 ], and likely could interfere with mRNA expression. Another, possible explanation is that it could be due to a phenomenon similar to transcriptional adaptation.…”

Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5)

“…The effect of cis -related genetic heterogeneity can underlie incomplete penetrance, allelic imbalance, and compensatory effects among other phenomena ( Cooper et al, 2013 ; Lopes-Marques et al, 2021 ; Serrano et al, 2021 ). Several studies have shown that the rs1805124 variant is able to act as a genetic modifier of many SCN5A disease-associated variants ( e.g .…”

“…Mendelian monogenic diseases often show clinical heterogeneity, so that individuals carrying the same variant can manifest different phenotypes. This may result from epistatic interactions between variants highlighting the importance of the genetic background in the phenotypic characteristics each individual manifests ( Fournier & Schacherer, 2017 ; Lehner, 2011 ; Lopes-Marques et al, 2021 ; Suriano et al, 2007 ). The importance of genetic architecture is well illustrated in the particular case of co-occurrence of polymorphic and deleterious variants in the same protein.…”