Delineation of functionally essential protein regions for 242 neurodevelopmental genes

Journal
Brain
ISSN
0006-8950
1460-2156
Date Issued
2022
Author(s)
Sumaiya Iqbal
Tobias Brünger
Marie Macnee
Andreas Brunklaus
Mark J Daly
Arthur J Campbell
David Hoksza
Patrick May
Dennis Lal
Lorena Diaz
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85153479909
WoS ID
WOS:000914653300001
DOI
URL
URL Institutional Repository
Abstract
<jats:title>Abstract</jats:title>
<jats:p>Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants.</jats:p>
<jats:p>We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including &gt;360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.</jats:p>
<jats:p>In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.</jats:p>
Cite this document
Iqbal, S., Brünger, T., Pérez-Palma, E., Macnee, M., Brunklaus, A., Daly, M. J., Campbell, A. J., Hoksza, D., May, P., & Lal, D. (2023). Delineation of functionally essential protein regions for 242 neurodevelopmental genes. Brain, 146(2), 519-533. https://doi.org/10.1093/brain/awac381
Dataset(s)
Subjects
bioinformatics

; 

genetics

; 

neurodevelopmental disorder

; 

4 aminobutyric acid receptor

; 

binding protein

; 

elongation factor

; 

elongation factor 1alpha2

; 

glucose transporter

; 

guanine nucleotide binding protein

; 

n methyl dextro aspartic acid receptor

; 

phosphatase

; 

phosphoprotein phosphatase 2a

; 

phosphotransferase

; 

potassium channel

; 

sodium channel

; 

syntaxin 1

; 

syntaxin binding protein 1

; 

unclassified drug

; 

voltage gated calcium channel

; 

amino acid sequence

; 

article

; 

autism

; 

binding site

; 

bioinformatics

; 

complex formation

; 

controlled study

; 

developmental delay

; 

developmental disorder

; 

enzyme active site

; 

epilepsy

; 

genetic variability

; 

haploinsufficiency

; 

human

; 

intellectual impairment

; 

ligand binding

; 

mental disease

; 

missense mutation

; 

paralogy

; 

protein data bank

; 

protein dephosphorylation

; 

protein dna binding

; 

protein folding

; 

protein function

; 

protein protein interaction

; 

protein structure

; 

whole exome sequencing