In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia

AbstractMutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

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In Silico analysis of SIGMAR1 gene causing distal hereditary motor neuropathy in a Pakistani family

Gene Reports ◽

10.1016/j.genrep.2019.100445 ◽

2019 ◽

Vol 16 ◽

pp. 100445

Author(s):

Sarmad Mehmood ◽

Gaurav V. Harlalka ◽

Rubina Dad ◽

Barry A. Chioza ◽

Muhammad I. Ullah ◽

...

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Motor Neuropathy ◽

Pakistani Family ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy ◽

Silico Analysis

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Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

PLoS ONE ◽

10.1371/journal.pone.0247841 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247841

Author(s):

Gabriel Rodrigues Coutinho Pereira ◽

Bárbara de Azevedo Abrahim Vieira ◽

Joelma Freire De Mesquita

Keyword(s):

Molecular Dynamics ◽

Amino Acids ◽

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

In Silico ◽

In Silico Analysis ◽

The United States ◽

Missense Mutations ◽

Superoxide Dismutase 1 ◽

Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.

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