Decoding disease-causing mechanisms of missense mutations from supramolecular structures

Abstract

The inheritance modes of pathogenic missense mutations are known to be highly associated with protein structures; recessive mutations are mainly observed in the buried region of protein structures, whereas dominant mutations are significantly enriched in the interfaces of molecular interactions. However, the differences in phenotypic impacts among various dominant mutations observed in individuals are not fully understood. In the present study, the functional effects of pathogenic missense mutations on three-dimensional macromolecular complex structures were explored in terms of dominant mutation types, namely, haploinsufficiency, dominant-negative, or toxic gain-of-function. The major types of dominant mutation were significantly associated with the different types of molecular interactions, such as protein-DNA, homo-oligomerization, or intramolecular domain-domain interactions, affected by mutations. The dominant-negative mutations were biased toward molecular interfaces for cognate protein or DNA. The haploinsufficiency mutations were enriched on the DNA interfaces. The gain-of-function mutations were localized to domain-domain interfaces. Our results demonstrate a novel use of macromolecular complex structures for predicting the disease-causing mechanisms through inheritance modes.

WITHDRAWN: Molecular Insight Into the Mutation Within Critical Zinc2+-Binding Site in the PAS Domain of WalK in Vancomycin-Intermediate Resistant Staphylococcus Aureus

“…WalK. The destabilizing effect of mutations on protein leads to signi cant disruption of protein function or its regulation 40 . Here, decreasing the a nity of WalK interactions (with proteins and nucleic acids) in VAN-I mutant was con rmed by the downregulation of walKR and walKR-regulated autolysins (sle1, lytM, and atlA).…”

Dynactin1 depletion leads to neuromuscular synapse instability and functional abnormalities

“…Along with the reduced DCNT1 mRNA and protein levels reported in sporadic ALS patients [26], missense mutations in DCTN1 have been reported in ALS patients [28–30, 32]. In the context of a dominant inheritance, these missense mutations could likely lead to haploinsufficiency, as one out of three outcomes of missense mutation [85]. In further support of this hypothesis, it was reported that animal models for Dynactin1 mutations lead to a reduction in protein expression, for instance in the G59S mice [50], or the G38S flies [51], however the effect of other ALS-related mutations on protein expression was not studied.…”

Genome-wide association studies and genetic testing: understanding the science, success, and future of a rapidly developing field

“…Generally speaking, the mutations associated with recessive Mendelian diseases most commonly inactivate the affected gene (also known as loss-of-function mutations), whereas the mutations associated with dominant Mendelian diseases most commonly result in increased gene expression (also known as gain-of-function mutations). 13 Notably, any type of mutation can result in alterations to gene products that can result in new or interfering functions, but this is most commonly associated with dominant, gain-of-function mutations.…”