Structural Principles Governing Disease-Causing Germline Mutations

Advancements in sequencing in the past decades enabled not only the determination of the human proteome but also the identification of a large number of genetic variations in the human population. The phenotypic effects of these mutations range from neutral for polymorphisms to severe for some somatic mutations. Disease-causing germline mutations (DCMs) represent a special and largely understudied class with relatively weak phenotypes. While for somatic mutations their effect on protein structure and regulation has been extensively studied in select cases, for germline mutations, this information is currently largely missing. In this analysis, a large amount of DCMs were analyzed and contrasted to polymorphisms from a structural point of view. Our results delineate the characteristic features of DCMs starting at the global level of partitioning proteins into globular, disordered and transmembrane classes, moving toward smaller structural units describing secondary structure elements and molecular surfaces, reaching down to the smallest structural entity, post-translational modifications. We show how these structural entities influence the emergence and possible phenotypic effects of DCMs.