Identification of L84F mutation with a novel nucleotide change c.255G > T in the superoxide dismutase gene in a North Indian family with amyotrophic lateral sclerosis

Abstract

Mutations in the superoxide dismutase (SOD1) gene account for ∼15% and in the transactive response DNA binding protein (TARDBP) gene for ∼5% of familial amyotrophic lateral sclerosis (FALS) cases. These two genes were analysed in two siblings from North India with ALS and a positive family history. The coding region of SOD1 and TARDBP genes was sequenced in both siblings. Genetic variation identified in SOD1 was typed in unaffected family members (n = 11), sporadic ALS patients (n = 48) and healthy controls (n = 35). Molecular dynamic (MD) simulations were performed on wild-type (WT) and mutant monomers of SOD1 to determine structural changes due to the identified mutation. A novel heterozygous nucleotide variation (c.255G > T) was identified in exon 4 of SOD1 in the two siblings and two asymptomatic family members but not in SALS patients and healthy controls. This variation results in a known non-synonymous substitution from leucine to phenylalanine at position 84 (L84F), making it a triallelic variation. Large conformational changes were observed in the zinc loop and electrostatic loop in an L84F mutant compared to WT SOD1 in MD simulations. In conclusion, this is the first report of mutation in SOD1 associated with FALS in India. Structural perturbations in L84F SOD1 may cause dimer destabilization, with decreased metal affinity leading to oligomerization.

Key words:

• Familial amyotrophic lateral sclerosis
• superoxide dismutase
• L84F
• c.255G > T
• molecular dynamic simulations

Acknowledgements

We acknowledge the CSIR4PI supercomputing facility. VT acknowledges funding from the Research Development Programme of Sir Ganga Ram Hospital, India. AV and MV acknowledge the Junior and Senior Research Fellowships, respectively, from the Indian Council of Medical Research. We also thank Veronique Dinand for discussions and suggestions.

Declaration of interest

The authors have no other financial, consulting, or personal involvement with any organization or entity with a financial interest or conflict with the subject matter or materials discussed in the manuscript.