Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes

Abstract

Neurodevelopmental disorders such as intellectual disability, autism spectrum disorder and schizophrenia lack precise boundaries in their clinical definitions, epidemiology, genetics and protein-protein interactomes. This calls into question the appropriateness of current categorical disease concepts. Recently, there has been a rising tide to reformulate neurodevelopmental nosological entities from biology upward. To facilitate this developing trend, we propose that identification of unique proteomic signatures that can be strongly associated with patient's risk alleles and proteome-interactome-guided exploration of patient genomes could define biological mechanisms necessary to reformulate disorder definitions.

Figure 1

DTNBP1–dysbindin interactomes differ in their constituents and topology. Interactomes were assembled with the Dapple algorithm (http://www.broadinstitute.org/mpg/dapple/dapple.php) using as inputs the dysbindin associated proteins identified by affinity chromatography (a), and interactors reported in three protein–protein interaction databases: (b) Biogrid (http://thebiogrid.org/), (c) Genemania (http://www.genemania.org/) and (d) String 9.05 (http://string.embl.de/). Red boxes highlight DTNBP1. Note that the identity of interacting proteins differs among interactomes. Color code represents a Dapple estimated probability that a protein would be as connected to other proteins (directly or indirectly) by chance as is depicted. Only interactome A presents a biochemically and genetically confirmed interaction between the adaptor complex AP-3 and the dysbindin-containing BLOC-1 complex.

Figure 2

Models of cross-fertilization between genomes, proteomes and interactomes. Grid in diagrams (a) to (e) depicts a polygenic genetic landscape associated with a NDD. Circles represent defined genes within the grid that when affected in different combinations trigger a NDD. Bars above each gene indicate a subject where a gene defect was found on a GWAS. Blue bars are those subjects that have a defect in a gene below statistical threshold, which is marked by the asterisk in (a). Red bars above a gene represent subjects that have a defect in a gene above statistical threshold. (b) Depicts a ‘tip of the iceberg gene α' and the network to which it belongs represented by the connected red circles (interactome 1). (c) Depicts three ‘tip of the iceberg genes' and the network to which they belong (interactome 1). The yellow interactome 2 is constituted by genes below statistical threshold as defined by gene-centric GWAS statistical analysis. (d) Represents genetic defects (blue bars) in two interactomes per patient (subjects 1–3). Note that in all patients there are no gene defects in the red interactome. E depicts hypothetical results of an interactome-centric GWAS that includes subjects 1–3 in (d). The yellow interactome 2 is now above statistical threshold as defined by an interactome-centric GWAS statistical analysis. See text for details.