Genetic variation associated with condensate dysregulation in disease.

TitleGenetic variation associated with condensate dysregulation in disease.
Publication TypeJournal Article
Year of Publication2022
AuthorsBanani SF, Afeyan LK, Hawken SW, Henninger JE, Dall'Agnese A, Clark VE, Platt JM, Oksuz O, Hannett NM, Sagi I, Lee TIhn, Young RA
JournalDev Cell
Volume57
Issue14
Pagination1776-1788.e8
Date Published2022 Jul 25
ISSN1878-1551
KeywordsHumans, Mutation, Proteins
Abstract

A multitude of cellular processes involve biomolecular condensates, which has led to the suggestion that diverse pathogenic mutations may dysregulate condensates. Although proof-of-concept studies have identified specific mutations that cause condensate dysregulation, the full scope of the pathological genetic variation that affects condensates is not yet known. Here, we comprehensively map pathogenic mutations to condensate-promoting protein features in putative condensate-forming proteins and find over 36,000 pathogenic mutations that plausibly contribute to condensate dysregulation in over 1,200 Mendelian diseases and 550 cancers. This resource captures mutations presently known to dysregulate condensates, and experimental tests confirm that additional pathological mutations do indeed affect condensate properties in cells. These findings suggest that condensate dysregulation may be a pervasive pathogenic mechanism underlying a broad spectrum of human diseases, provide a strategy to identify proteins and mutations involved in pathologically altered condensates, and serve as a foundation for mechanistic insights into disease and therapeutic hypotheses.

DOI10.1016/j.devcel.2022.06.010
Alternate JournalDev Cell
PubMed ID35809564
PubMed Central IDPMC9339523
Grant ListR01 MH104610 / MH / NIMH NIH HHS / United States
F32 CA254216 / CA / NCI NIH HHS / United States
T32 DK007191 / DK / NIDDK NIH HHS / United States
T32 CA251062 / CA / NCI NIH HHS / United States
P01 CA155258 / CA / NCI NIH HHS / United States
T32 GM087237 / GM / NIGMS NIH HHS / United States
R01 GM123511 / GM / NIGMS NIH HHS / United States
F31 CA250171 / CA / NCI NIH HHS / United States