A novel codon4 mutation (A4F) in the SOD1gene in familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the selective loss of motor neurons. Approximately 5% to 10% of patients with ALS have a family history of the disease, and approximately 20% of familial amyotrophic lateral sclerosis (fALS) cases are associated with mutations in Cu/Zn superoxide dismutase (SOD1). In this study, we evaluated the structural and functional effects of human A4F and A4V SOD1 protein mutations. We performed an in silico analysis using prediction algorithms of nonsynonymous single‐nucleotide polymorphisms (nsSNPs) associated with the fALS development. Our structural conservation results show that the mutations analyzed (A4V and A4F) were in a highly conserved region. Molecular dynamics simulations using the Linux GROMACS package revealed how these mutations affect protein structure, protein stability, and aggregation. These results suggest that there might be an effect on the SOD1 function. Understanding the molecular basis of disease provides new insights useful for rational drug design and advancing our understanding of the ALS development.

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“…The stability of the A4V variant of SOD1 might underlie its toxic effects, which were previously described. 32…”

Section: Sequence and Natural Variants Retrievalmentioning

confidence: 99%

SOD1 in amyotrophic lateral sclerosis development – in silico analysis and molecular dynamics of A4F and A4V variants

Silva

Pereira

Moreira

et al. 2019

J of Cellular Biochemistry

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“… 1 2 However, a pathogenic variant of TARDBP has not been reported in Korea. 3 4 Herein we report a pathogenic variant of TARDBP in a Korean patient with familial ALS.…”

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confidence: 96%

First Case of TARDBP-Related Amyotrophic Lateral Sclerosis in Korea

et al. 2020

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Dear Editor Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons. The cause of most cases of ALS is unknown, but 5-10% of them can be attributed to genetic alterations. 1 Currently, 71 causative genes have been identified as causing familial ALS (www.musclegenetable.fr). Among them, C9ORF72 and SOD1 are the most common causative genes in European and Asian populations, respectively. Additionally, alterations in TARDBP and FUS each account for approximately 5% of patients with familial ALS. 1,2 However, a pathogenic variant of TARDBP has not been reported in Korea. 3,4 Herein we report a pathogenic variant of TARDBP in a Korean patient with familial ALS. A 52-year-old male (II-11) (Fig. 1A) was referred to our institute with progressive muscle weakness. He had a family history of ALS in his mother (I-2) and elder sister (II-4), who had progressive asymmetric muscle weakness and died from respiratory failure in their 60s and 50s, respectively. The muscle weakness and wasting in the index patient had started in his right leg at the age of 50 years and progressed to his left leg and arm. A physical examination showed muscle weakness, wasting, and fasciculations in both legs and the left arm. The deep tendon reflexes in the bilateral knees and left arm were hyperactive. However, cognitive dysfunction, sensory deficits, and ataxia were not found. Magnetic resonance imaging showed only mild parenchymal atrophy in the brain and spinal cord. An electrophysiological examination revealed a widespread neurogenic process without sensory nerve involvement in the cervical, thoracic, and lumbosacral segments. The patient was diagnosed with clinically probable ALS, after which we performed targeted sequencing of 172 neuropathy-related genes (Supplementary Table 1 in the online-only Data Supplement) and identified a heterozygous pathogenic variant of TARDBP (NM_007375.4: c.1009A>G; NP_031401.1:p.M337V) (Fig. 1B). This variant was previously reported as a pathogenic variant in ALS. 2 We speculate that the c.1009A>G variant should be classified as a likely pathogenic variant based on the following evidence: 1) located in a mutational hotspot without benign variation, 2) not in Genome Aggregation Database (gnomAD), 3) low rate of benign missense variation in TARDBP, 4) multiple lines of computational evidence supporting a deleterious effect on the gene, 5) a well-established in-vivo functional study having supported a damaging effect on the gene, and 6) many previous reports of it being a pathogenic variant. 2,5,6 The TDP-43 protein encoded by TARDBP is a widely expressed RNA/DNA-binding protein involved in the regulation of RNA processing and other cellular functions. 7 Most pathogenic variants of TARDBP (including c.1009A>G) are located in the C-terminal glycine-rich domain. An abnormal C-terminal domain is believed to improve the aggregation propensity of the TDP-43 protein, which results in neurodegeneration. However, it is unclear whether the path...

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“…The observed variability in the clinical phenotype dependent on the substituted amino acid at the same codon of SOD1 was consistent with previous findings. 1 , 7 …”

Section: Discussionmentioning

confidence: 99%

“…The family history based on interviews with the patient and his relatives was suggestive of an autosomal-dominant inheritance. Direct sequencing analyses of SOD1 in the patient using a previously described method 1 revealed a novel missense mutation (c.137T>C; F45S). The patient's mother had died at age 72 years, only 1 year after being diagnosed with ALS, while his younger sister had died 8 months after being diagnosed with ALS, at the age of 52 years ( Table 1 ).…”

Section: Case Reportmentioning

confidence: 99%

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Novel F45SSOD1Mutation in Amyotrophic Lateral Sclerosis Coexisting with Bullous Pemphigoid

Hong

Choi

et al. 2015

J Clin Neurol

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BackgroundThe coexistence of an autoimmune disease and amyotrophic lateral sclerosis (ALS) has led to the hypothesis that immune-mediated pathological mechanisms are overlapping in the two diseases. We report herein a rare coexistence of bullous pemphigoid (BP) in a novel mutation (F45S) of the gene encoding Cu/Zn superoxide dismutase (SOD1) in an ALS patient, and discuss a role for the SOD1 mutation in this unusual overlap.Case ReportA 57-year-old male with familial ALS, including vesicles and tense bullae on erythematous bases, was diagnosed with BP. Direct immunofluorescence revealed deposits of C3 and immunoglobulin G in the basement membrane zone. Direct sequencing of SOD1 in the patient revealed a novel mutation (c.137T>C; F45S).ConclusionsWe report a novel SOD1 mutation in ALS, which was combined with BP. This novel SOD1 mutation could affect the phenotype of a combined autoimmune disease and matrix metalloproteinase-9. There may therefore be common factors linking BP and ALS with the SOD1 mutation.

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A novel codon4 mutation (A4F) in the SOD1gene in familial amyotrophic lateral sclerosis

Cited by 13 publications

References 17 publications

SOD1 in amyotrophic lateral sclerosis development – in silico analysis and molecular dynamics of A4F and A4V variants

SOD1 in amyotrophic lateral sclerosis development – in silico analysis and molecular dynamics of A4F and A4V variants

First Case of TARDBP-Related Amyotrophic Lateral Sclerosis in Korea

Novel F45SSOD1Mutation in Amyotrophic Lateral Sclerosis Coexisting with Bullous Pemphigoid

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