Landscape of pleiotropic proteins causing human disease: structural and system biology insights
File(s)
Accepted version
Author(s)
Ittisoponpisan, S
Sternberg, MJE
Alhuzimi, E
David, A
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.
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.
Date Issued
2017-01-11
Date Acceptance
2016-12-03
Citation
Human Mutation, 2017, 38 (3), pp.289-296
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
Medical Research Council
Grant Number
MR/K021613/1
Subjects
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
0604 Genetics
1103 Clinical Sciences
Publication Status
Published