Dissecting disease inheritance modes in a three-dimensional protein network challenges the "guilt-by-association" principle. Academic Article uri icon

Overview

MeSH

  • Alleles
  • Antigens, Differentiation
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Genetic Association Studies
  • Genetic Diseases, Inborn
  • Genetic Heterogeneity
  • Genetic Loci
  • Humans
  • Mutation
  • Neoplasms
  • Nuclear Proteins
  • Receptors, Immunologic

MeSH Major

  • Genetic Predisposition to Disease
  • Inheritance Patterns
  • Protein Interaction Mapping
  • Protein Interaction Maps

abstract

  • To better understand different molecular mechanisms by which mutations lead to various human diseases, we classified 82,833 disease-associated mutations according to their inheritance modes (recessive versus dominant) and molecular types (in-frame [missense point mutations and in-frame indels] versus truncating [nonsense mutations and frameshift indels]) and systematically examined the effects of different classes of disease mutations in a three-dimensional protein interactome network with the atomic-resolution interface resolved for each interaction. We found that although recessive mutations affecting the interaction interface of two interacting proteins tend to cause the same disease, this widely accepted "guilt-by-association" principle does not apply to dominant mutations. Furthermore, recessive truncating mutations in regions encoding the same interface are much more likely to cause the same disease, even for interfaces close to the N terminus of the protein. Conversely, dominant truncating mutations tend to be enriched in regions encoding areas between interfaces. These results suggest that a significant fraction of truncating mutations can generate functional protein products. For example, TRIM27, a known cancer-associated protein, interacts with three proteins (MID2, TRIM42, and SIRPA) through two different interfaces. A dominant truncating mutation (c.1024delT [p.Tyr342Thrfs*30]) associated with ovarian carcinoma is located between the regions encoding the two interfaces; the altered protein retains its interaction with MID2 and TRIM42 through the first interface but loses its interaction with SIRPA through the second interface. Our findings will help clarify the molecular mechanisms of thousands of disease-associated genes and their tens of thousands of mutations, especially for those carrying truncating mutations, often erroneously considered "knockout" alleles. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

publication date

  • July 11, 2013

has subject area

  • Alleles
  • Antigens, Differentiation
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Genetic Association Studies
  • Genetic Diseases, Inborn
  • Genetic Heterogeneity
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Humans
  • Inheritance Patterns
  • Mutation
  • Neoplasms
  • Nuclear Proteins
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Receptors, Immunologic

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3710751

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2013.05.022

PubMed ID

  • 23791107

Additional Document Info

start page

  • 78

end page

  • 89

volume

  • 93

number

  • 1