Missense Mutations of Codon 116 in the SOD1 Gene Cause Rapid Progressive Familial ALS and Predict Short Viability With PMA Phenotype

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, characterized by a great variety of both clinical presentations and genetic causes. Previous studies had identified two different missense mutations in SOD1 (p.R116C and p.R116G) causing familial ALS. In this study, we report a novel heterozygous missense mutation in the SOD1 gene (p.R116S) in a family with inherited ALS manifested as fast-deteriorating pure lower motor neuron symptoms. The patient displayed similar clinical picture and prognostic value to previous reported cases with different R116 substitution mutations. Modeling of all R116 substitutions in the resolved SOD1 protein structure revealed a shared mechanism with destroyed hydrogen bonds between R116 and other two residues, which might lead to protein unfolding and oligomer formation, ultimately conferring neurotoxicity.

Keywords: SOD1; amyotrophic lateral sclerosis; lower motor neuron; progressive muscular atrophy; rapid progression.

FIGURE 1

(A) Pedigree of the family. Square = male; circle = female; diagonal black line = deceased individual; black filled symbol = clinically proven affected individual; empty symbol = clinically healthy relative; question mark = suspected; arrow = proband. (B) DTI reconstruction of the bilateral cortical spinal tracts of the proband. RCST, right cortical spinal tract. LCST, left cortical spinal tract. (C) Confirmation by Sanger sequencing showing point mutation (red oval). (D) Sequence alignment analysis of SOD1 in different species. Amino acid at position 116 is highlighted in red. (E) Functional prediction of mutations at 116th amino acid in SOD1.

FIGURE 2

Structural modeling of the ALS-associated SOD1 R116 mutants in the study. (A) Monomer views of the SOD1 homodimer (PDB: 2c9v). Mutations discussed in Table 1 are highlighted and annotated. (B–E) Close lookup views of the hydrogen bonds (yellow dash line) for R116 and mutants R116S, R116G, and R116C, respectively.