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.

Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes

“…On one hand, the same genetic defect generates more than one disorder. On the other hand, the same disorder is produced by single copy loss of different loci (72)(73)(74). Mechanisms by which these single copy losses generate neurodevelopmental and cognition defects are not understood.…”

Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

“…These findings strongly suggest that the Arp2/3 and, by extension, the mechanisms that control actin dynamics participate in the pathogenesis of diverse neurodevelopmental disorders. We emphasize that even when genetic evidence may not support the role of a molecule in a particular neurodevelopmental disorder, the interactome of that molecule may hold key mechanistic connections with genes genetically implicated in neurodevelopmental disorder risk (Barabasi et al, ; Mullin et al, ; Boyle et al, ).…”

Pallidin is a novel interacting protein for cytohesin‐2 and regulates the early endosomal pathway and dendritic formation in neurons

“…Furthermore, it has recently emerged as a common biological process affected by neurodevelopmental disorders such as schizophrenia, autism spectrum disorder, and intellectual disability (Ryder and Faundez ; Mullin et al . ), and neurodegenerative diseases such as lysosomal storage diseases, Parkinson's disease, and Alzheimer's disease (Schreij et al . ).…”