Despite that as much as 15 percent of the population develop neurodevelopmental disorders, still little is known about the truncated cellular processes potentially caused by structural modifications in the proteins. Not to mention, the share of intrinsic disorder is even smaller in the literature related to this matter. Although several studies demonstrated that coding Single Nucleotide Variants (SNVs) take vital parts in the etiology of neurodevelopmental disorders when it comes to Intrinsically Disordered Proteins (IDPs) the predictors of the pathogenic effect of the mutations lose their accuracy. Hence, in this work, bioinformatics tools were taken advantage of to investigate the coding variants within Intrinsically Disordered Regions (IDRs) of the proteins based on 679 candidate genes from Gene4denovo-collected exome studies. These proteins are selected for 6 NDD phenotypes making up a list of 1308 proteins. Furthermore, the importance of protein disorder in the emergence of these phenotypes is being assessed considering intrinsic disorder hooked structural characteristics, post-translational modifications, and liquid-liquid phase separation. Homo sapiens and brain protein sets were created for comparison reasons. The frequency of variants occurring in IDRs was comparable among phenotypes with the amount being always lower for homo sapiens and brain in comparison to NDD phenotypes. When looking at NDD-associated proteins in phase separation, the amount of variants in disordered regions is even higher with a median variant fraction falling at 0.6. Finally, factors that alter intrinsically disordered protein regulation or function may lead to disease. The closer we approach the underlying causes of these disorders, the better we get at figuring out new therapeutics. To achieve this, variants with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies.

How Disordered are neurodevelopmental disorders?

KORDEVANI, FATEMEH
2021/2022

Abstract

Despite that as much as 15 percent of the population develop neurodevelopmental disorders, still little is known about the truncated cellular processes potentially caused by structural modifications in the proteins. Not to mention, the share of intrinsic disorder is even smaller in the literature related to this matter. Although several studies demonstrated that coding Single Nucleotide Variants (SNVs) take vital parts in the etiology of neurodevelopmental disorders when it comes to Intrinsically Disordered Proteins (IDPs) the predictors of the pathogenic effect of the mutations lose their accuracy. Hence, in this work, bioinformatics tools were taken advantage of to investigate the coding variants within Intrinsically Disordered Regions (IDRs) of the proteins based on 679 candidate genes from Gene4denovo-collected exome studies. These proteins are selected for 6 NDD phenotypes making up a list of 1308 proteins. Furthermore, the importance of protein disorder in the emergence of these phenotypes is being assessed considering intrinsic disorder hooked structural characteristics, post-translational modifications, and liquid-liquid phase separation. Homo sapiens and brain protein sets were created for comparison reasons. The frequency of variants occurring in IDRs was comparable among phenotypes with the amount being always lower for homo sapiens and brain in comparison to NDD phenotypes. When looking at NDD-associated proteins in phase separation, the amount of variants in disordered regions is even higher with a median variant fraction falling at 0.6. Finally, factors that alter intrinsically disordered protein regulation or function may lead to disease. The closer we approach the underlying causes of these disorders, the better we get at figuring out new therapeutics. To achieve this, variants with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies.
2021
How Disordered are neurodevelopmental disorders? (The involvement of intrinsically disordered proteins in neurodevelopmental disorders)
Intrinsic disorder
neurodevelopmental
ndd
disordered proteins
disorders
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12608/33073