Rare Angiogenin and Ribonuclease 4 variants associated with amyotrophic lateral sclerosis exhibit loss-of-function: a comprehensive in silico study

Metabolic Brain Disease
Aditya K PadhiJames Gomes

Abstract

Amyotrophic Lateral Sclerosis (ALS), a debilitating neurodegenerative disorder is related to mutations in a number of genes, and certain genes of the Ribonuclease (RNASE) superfamily trigger ALS more frequently. Even though missense mutations in Angiogenin (ANG) and Ribonuclease 4 (RNASE4) have been previously shown to cause ALS through loss-of-function mechanisms, understanding the role of rare variants with a plausible explanation of their functional loss mechanisms is an important mission. The study aims to understand if any of the rare ANG and RNASE4 variants catalogued in Project MinE consortium caused ALS due to loss of ribonucleolytic or nuclear translocation or both these activities. Several in silico analyses in combination with extensive molecular dynamics (MD) simulations were performed on wild-type ANG and RNASE4, along with six rare variants (T11S-ANG, R122H-ANG, D2E-RNASE4, N26K-RNASE4, T79A-RNASE4 and G119S-RNASE4) to study the structural and dynamic changes in the catalytic triad and nuclear localization signal residues responsible for ribonucleolytic and nuclear translocation activities respectively. Our comprehensive analyses comprising 1.2 μs simulations with a focus on physicochemical, structural and dynamic...Continue Reading

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Methods Mentioned

BETA
nuclear translocation
in silico methods
nuclear

Software Mentioned

Mutation Assesor
MinE browser
pred
Condel
MinE Variant Browser
VEP
PROVEAN ( Protein Variation Effect Analyzer )
PROVEAN Condel
Variant Effect Predictor ( VEP )
Mutation Assessor

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