Widespread macromolecular interaction perturbations in human genetic disorders

Area of Science:

• Genetics
• Molecular Biology
• Systems Biology

Background:

• Understanding how genetic mutations cause disease is crucial, yet the functional impact of most disease-associated variants remains unknown.
• Over 100,000 disease-associated variants lack functional characterization, hindering our understanding of disease mechanisms.
• Existing knowledge is limited to a few well-studied alleles, leaving a significant gap in functional information for the majority of variants.

Purpose of the Study:

• To functionally profile thousands of missense mutations linked to Mendelian disorders.
• To investigate how these mutations affect protein activities within biological networks.
• To differentiate between mutations that disrupt protein folding/stability versus those that alter specific interactions.

Main Methods:

• Utilized various interaction assays to functionally profile thousands of missense mutations.
• Assessed chaperone binding to evaluate protein folding and stability.
• Examined protein-protein interactions and DNA binding activities for disease-associated alleles.

Main Results:

• The majority of disease-associated alleles showed normal chaperone binding, indicating preserved protein folding or stability.
• Two-thirds of disease-associated alleles perturbed protein-protein interactions, with half being "edgetic" (affecting a subset of interactions).
• Mutations in transcription factors often affected DNA binding even when protein-protein interactions were intact; distinct mutations in the same gene yielded different interaction profiles and disease phenotypes.

Conclusions:

• Disease-associated alleles frequently impair specific protein activities, such as protein-protein interactions or DNA binding, rather than broadly affecting protein folding or stability.
• The concept of "edgetic" alleles, which subtly alter interaction networks, is widespread among disease-associated variants.
• Understanding these specific functional perturbations is key to deciphering disease mechanisms and potentially developing targeted therapies.