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

Abstract

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. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure: implications for variant effect prediction

“…This suggests that the precise molecular mechanisms underlying DN mutations could show some tendency to vary related to functional context. For example, while a DN effect can be caused by non-destabilising mutants that can incorporate into and “poison” a protein complex, there are also DN mutations that disrupt interactions, resulting in a “competitive” DN effect 39 .…”

First splicing variant in HECW2 with an autosomal recessive pattern of inheritance and associated with NDHSAL

“…Furthermore, HECW2 is intolerant to haploinsufficiency and loss‐of‐function (LOF), and hypomorphic variants (nonsense, frameshift, or variant in the catalytic cysteine 1540) with LOF have not been described to date (Acharya et al, 2021). This suggests that these missense variants could act through a gain‐of‐function (GOF) or dominant negative (DN) mechanism (Acharya et al, 2021; Backwell & Marsh, 2022). The DN variants act by interfering with the activity of wild‐type protein through competition, by competing with the wild‐type subunit in homomeric complexes or reducing the availability of free ligand for the wild‐type protein.…”

“…The DN variants act by interfering with the activity of wild‐type protein through competition, by competing with the wild‐type subunit in homomeric complexes or reducing the availability of free ligand for the wild‐type protein. On the other hand, the GOF variants act by increasing protein activity (hypermorphic) or introducing a new function (neomorphic), but the specific molecular mechanisms can be complex (Backwell & Marsh, 2022). It has been demonstrated previously that the four recurrent variants (p.(Arg1191Gln), p.(Asn1199Lys), p.(Phe1327Ser), and p.(Arg1330Trp)), showed a difference in protein surface property and conformation compared with wild‐type (Acharya et al, 2021).…”

Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations

“…This would typically be associated with the mutant protein retaining the ability to incorporate into microtubules, which has been observed for many pathogenic tubulin mutations (27)(28)(29)(30)(31)(32). For dominant-negative mutations, the incorporation of mutant protein directly or indirectly disrupts the activity of the wild-type protein (26). In these cases, the mutant tubulin retains its ability to form a heterodimer and assemble into microtubules before consequently impacting function in some other way, e.g.…”