Diverse Molecular Mechanisms Underlying Pathogenic Protein Mutations: Beyond the Loss-of-Function Paradigm

Lisa Backwell, Joseph A Marsh

Research output: Contribution to journalReview articlepeer-review

Abstract / Description of output

Most known disease-causing mutations occur in protein-coding regions of DNA. While some of these involve a loss of protein function (e.g., through premature stop codons or missense changes that destabilize protein folding), many act via alternative molecular mechanisms and have dominant-negative or gain-of-function effects. In nearly all cases, these non-loss-of-function mutations can be understood by considering interactions of the wild-type and mutant protein with other molecules, such as proteins, nucleic acids, or small ligands and substrates. Here, we review the diverse molecular mechanisms by which pathogenic mutations can have non-loss-of-function effects, including by disrupting interactions, increasing binding affinity, changing binding specificity, causing assembly-mediated dominant-negative and dominant-positive effects, creating novel interactions, and promoting aggregation and phase separation. We believe that increased awareness of these diverse molecular disease mechanisms will lead to improved diagnosis (and ultimately treatment) of human genetic disorders.

Original languageEnglish
Pages (from-to)475-498
JournalAnnual Review of Genomics and Human Genetics
Early online date8 Apr 2022
Publication statusPublished - 31 Aug 2022

Keywords / Materials (for Non-textual outputs)

  • activating mutations
  • dominant negative
  • gain of function
  • ligand binding
  • protein complexes
  • protein interactions


Dive into the research topics of 'Diverse Molecular Mechanisms Underlying Pathogenic Protein Mutations: Beyond the Loss-of-Function Paradigm'. Together they form a unique fingerprint.

Cite this