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

Hum Mutat. 2021 Aug;42(8):978-989. doi: 10.1002/humu.24221. Epub 2021 Jun 3.


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.

Keywords: OTC gene; enzymatic activity; genetic modifiers; pathogenic replacements; polymorphic variants; structural modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Humans
  • Mutation, Missense
  • Ornithine Carbamoyltransferase Deficiency Disease* / genetics
  • Ornithine Carbamoyltransferase* / genetics
  • Polymorphism, Genetic


  • OTC protein, human
  • Ornithine Carbamoyltransferase