Landscape of pleiotropic proteins causing human disease: structural and system biology insights

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Title: Landscape of pleiotropic proteins causing human disease: structural and system biology insights
Author(s): Ittisoponpisan, S
Sternberg, MJE
Alhuzimi, E
David, A
Item Type: Journal Article
Abstract: Pleiotropy is the phenomenon by which the same gene can result in multiple phenotypes. Pleiotropic proteins are emerging as important contributors to rare and common disorders. Nevertheless , little is known on the mechanisms underlying pleiotropy and the characteris tic of pleiotropic proteins. We analysed disease - causing proteins reported in Uni P rot and observed that 12% are pleiotropic ( variants in the same protein cause more than one disease). Pleiotropic proteins were enriched in deleterious and rare variants , bu t not in common variants . Pleiotropic proteins were more likely to be involved in the pathogenesis of n eoplasms, neurological and circulatory diseases, and congenital malformations, whereas non - pleiotropic proteins in endocrine and metabolic disorders . Pleiotropic proteins were more essential and ha d a higher number of interacting partners compared to non -pleiotropic proteins. S ignificantly more pleiotropic than non - pleiotropic proteins contained at least one intrinsically long disordered region (p<0.001 ). Deleterious variants occurring in structurally disordered regions were more commonly found in pleiotropic, rather than non - pleiotropic proteins. 14 In conclusion, pleiotropic proteins are an important contributor to human disease. They represent a biologi cally different class of proteins compared to non - pleiotropic proteins and a better understanding of their characteristics and genetic variants, can greatly aid in the interpretation of genetic studies and drug design.
Publication Date: 11-Jan-2017
Date of Acceptance: 3-Dec-2016
URI: http://hdl.handle.net/10044/1/43037
DOI: https://dx.doi.org/10.1002/humu.23155
ISSN: 1098-1004
Publisher: Wiley
Start Page: 289
End Page: 296
Journal / Book Title: Human Mutation
Volume: 38
Issue: 3
Copyright Statement: © 2016 Wiley Periodicals, INC.
Sponsor/Funder: Medical Research Council
Funder's Grant Number: MR/K021613/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
pleiotropy
genetic variants
human disease
disordered protein region
INTRINSICALLY DISORDERED PROTEINS
POPULATION-BASED COHORT
REGION PREDICTIONS
COMPLEX TRAITS
CANCER-RISK
MUTATIONS
DATABASE
VINCULIN
GENES
OTX2
disordered protein region
genetic variants
human disease
pleiotropy
Genetics & Heredity
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Faculty of Natural Sciences



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