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. 2021 Nov 17:12:776831.
doi: 10.3389/fgene.2021.776831. eCollection 2021.

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

Xinmei Wen  1 , Wenjia Zhu  1 , Nan L Xia  2 , Qianwen Li  3   4 , Li Di  1 , Shu Zhang  1 , Hai Chen  1 , Yan Lu  1 , Min Wang  1 , Min Xu  1 , Suobin Wang  1 , Xin-Ming Shen  5 , Jie Lu  3   4 , Yuwei Da  1
Affiliations

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

Xinmei Wen et al. Front Genet. .

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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
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
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.
See this image and copyright information in PMC

References

    1. Abe K., Aoki M., Ikeda M., Watanabe M., Hirai S., Itoyama Y. (1996). Clinical Characteristics of Familial Amyotrophic Lateral Sclerosis with CuZn Superoxide Dismutase Gene Mutations. J. Neurol. Sci. 136, 108–116. 10.1016/0022-510x(95)00314-r - DOI - PubMed
    1. Aksoy H., Dean G., Elian M., Deng H. X., Deng G., Juneja T., et al. (2003). A4T Mutation in the SOD1 Gene Causing Familial Amyotrophic Lateral Sclerosis. Neuroepidemiology 22, 235–238. 10.1159/000070564 - DOI - PubMed
    1. Andersen P. M., Nilsson P., Keränen M. L., Forsgren L., Hägglund J., Karlsborg M., et al. (1997). Phenotypic Heterogeneity in Motor Neuron Disease Patients with CuZn-Superoxide Dismutase Mutations in Scandinavia. Brain 120 (Pt 10), 1723–1737. 10.1093/brain/120.10.1723 - DOI - PubMed
    1. Andersen P. M., Sims K. B., Xin W. W., Kiely R., O'neill G., Ravits J., et al. (2003). Sixteen Novel Mutations in the Cu/Zn Superoxide Dismutase Gene in Amyotrophic Lateral Sclerosis: a Decade of Discoveries, Defects and Disputes. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4, 62–73. 10.1080/14660820310011700 - DOI - PubMed
    1. Aoki M., Abe K., Houi K., Ogasawara M., Matsubara Y., Kobayashi T., et al. (1995). Variance of Age at Onset in a Japanese Family with Amyotrophic Lateral Sclerosis Associated with a Novel Cu/Zn Superoxide Dismutase Mutation. Ann. Neurol. 37, 676–679. 10.1002/ana.410370518 - DOI - PubMed