title: 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.
authors.affiliation: a Department of Research , Sir Ganga Ram Hospital , Rajinder Nagar , Delhi .|b Department of Biotechnology , Jamia Hamdard , Hamdard Nagar , New Delhi, Delhi .
authors.forename: Abhishek
authors.initials: A
authors.lastname: Vats
authors.affiliation: c Department of Neurophysiology , Sir Ganga Ram Hospital , Rajinder Nagar , Delhi .|d Department of Neurology , Institute of Human Behaviour and Allied Sciences , New Delhi .
authors.forename: Mandaville
authors.initials: M
authors.lastname: Gourie-Devi
authors.affiliation: e CSIR-Institute of Genomics and Integrative Biology , Mall Road , New Delhi , and.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Verma
authors.affiliation: f CSIR-Institute of Genomics and Integrative Biology , Mathura Road , New Delhi, Delhi , India.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: f CSIR-Institute of Genomics and Integrative Biology , Mathura Road , New Delhi, Delhi , India.
authors.forename: Bhupesh
authors.initials: B
authors.lastname: Taneja
authors.affiliation: e CSIR-Institute of Genomics and Integrative Biology , Mall Road , New Delhi , and.
authors.forename: Ritushree
authors.initials: R
authors.lastname: Kukreti
authors.affiliation: a Department of Research , Sir Ganga Ram Hospital , Rajinder Nagar , Delhi .
authors.forename: Vibha
authors.initials: V
authors.lastname: Taneja
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007194:India / Q000453:epidemiology; D008239:Lysine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010649:Phenylalanine / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000072105:Superoxide Dismutase-1 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; D010649:Phenylalanine; D000072105:Superoxide Dismutase-1; D008239:Lysine
keywords: Familial amyotrophic lateral sclerosis; L84F; c.255G > T; molecular dynamic simulations; superoxide dismutase