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      High-Resolution Melting (HRM) Analysis of the Cu/Zn Superoxide Dismutase (SOD1) Gene in Japanese Sporadic Amyotrophic Lateral Sclerosis (SALS) Patients

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          Abstract

          Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and the majority of ALS are sporadic (SALS). Recently, several causative genes for familial ALS (FALS) were identified, but the cause of the SALS is still unknown. This time, we aimed to identify the genetic background of SALS. First, we applied the new sensitive screening methods: high-resolution melting (HRM) analysis. HRM analysis detected 18 out of 19 known SOD1 gene mutations (94.7% sensitivity). Next, we screened SOD1, three novel mutations (C6Y, Q22H, and S134T) were identified in our own 184 SALS cases (1.63% prevalence), and four mutations in another 255 SALS cases (1.56% prevalence) registered from all over Japan. The patients with SOD1 mutations suggested a relatively young onset and limb involvement at onset. The HRM analysis is a sensitive and easy screening method; we will use this method for screening other ALS causative genes and revealing the genetic background of SALS.

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          Most cited references26

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          High-resolution genotyping by amplicon melting analysis using LCGreen.

          Carl T. Wittwer, Gudrun H. Reed, Cameron N. Gundry … (2003)
          High-resolution amplicon melting analysis was recently introduced as a closed-tube method for genotyping and mutation scanning (Gundry et al. Clin Chem 2003;49:396-406). The technique required a fluorescently labeled primer and was limited to the detection of mutations residing in the melting domain of the labeled primer. Our aim was to develop a closed-tube system for genotyping and mutation scanning that did not require labeled oligonucleotides. We studied polymorphisms in the hydroxytryptamine receptor 2A (HTR2A) gene (T102C), beta-globin (hemoglobins S and C) gene, and cystic fibrosis (F508del, F508C, I507del) gene. PCR was performed in the presence of the double-stranded DNA dye LCGreen, and high-resolution amplicon melting curves were obtained. After fluorescence normalization, temperature adjustment, and/or difference analysis, sequence alterations were distinguished by curve shape and/or position. Heterozygous DNA was identified by the low-temperature melting of heteroduplexes not observed with other dyes commonly used in real-time PCR. The six common beta-globin genotypes (AA, AS, AC, SS, CC, and SC) were all distinguished in a 110-bp amplicon. The HTR2A single-nucleotide polymorphism was genotyped in a 544-bp fragment that split into two melting domains. Because melting curve acquisition required only 1-2 min, amplification and analysis were achieved in 10-20 min with rapid cycling conditions. High-resolution melting analysis of PCR products amplified in the presence of LCGreen can identify both heterozygous and homozygous sequence variants. The technique requires only the usual unlabeled primers and a generic double-stranded DNA dye added before PCR for amplicon genotyping, and is a promising method for mutation screening.
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            Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.

            M Cudkowicz, D McKenna-Yasek, P E Sapp … (1997)
            We registered 366 families in a study of dominantly inherited amyotrophic lateral sclerosis. Two hundred ninety families were screened for mutations in the gene encoding copper-zinc cytosolic superoxide dismutase (SOD1). Mutations were detected in 68 families. The most common SOD1 mutation is an alanine for valine substitution in codon 4 (50%). We present clinical and genetic data concerning 112 families with 395 affected individuals. The clinical characteristics of patients with familial amyotrophic lateral sclerosis arising from SOD1 mutations are similar to those lacking SOD1 defects. Mean age at onset was earlier (Wilcoxon test, p = 0.004) in the SOD1 group (46.9 years [standard deviation, 12.5] vs 50.5 years [11.5] in the non-SOD1 group). Bulbar onset was associated with a later onset age. The presence of either of two mutations, G37R and L38V, predicted an earlier age at onset. Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times (Wilcoxon test, p = 0.0007). The presence of one mutation, A4V, correlated with shorter survival. G37R, G41D, and G93C mutations predicted longer survival. This information suggests it will be productive to investigate other genetic determinants in amyotrophic lateral sclerosis and to use epidemiological characteristics of the disease to help discern molecular mechanisms of motor neuron cell death.
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              Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.

              Judith P. Andersen (2005)
              This review highlights recent epidemiologic, clinical-genetic, and neurochemical advances in our understanding of sporadic amyotrophic lateral sclerosis (ALS) and their relationships to familial ALS caused by superoxide dismutase (SOD1) gene mutations. It is of fundamental importance to recognize that ALS is a biologically heterogeneous syndrome in which genetics, environment, and aging are inter-related. The discovery of mutations in the SOD1 gene is the greatest breakthrough in ALS research since Charcot's description of the disorder, but the putative toxic gain of function of mutant SOD1 remains elusive despite intense research. Currently, two dominant theories for the pathogenesis of SOD1 mutations exist: specific protein cytotoxicity and protein aggregation. Mutant SOD1 interacts specifically with neurofilament-light chain mRNA and the dynein/dynactin complex, suggesting that cytoskeletal defects and axonal transport are key players. In addition, mutant SOD1 protein has increased propensity to form aggregate-prone monomers, and the degree of instability correlates inversely with length of survival; therefore, increased propensity to aggregate may be the unifying common denominator for the 119 diverse SOD1 mutations.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neurol Res Int
                Journal ID (publisher-id): NRI
                Title: Neurology Research International
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2090-1852
                ISSN (Electronic): 2090-1860
                Publication date (Print): 2011
                Publication date (Electronic): 12 April 2011
                Volume: 2011
                Electronic Location Identifier: 165415
                Affiliations
                1Division of Neurology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan
                2Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya-shi, Aichi 466-8550, Japan
                Author notes

                Academic Editor: Dirk Deleu

                Article
                DOI: 10.1155/2011/165415
                PMC ID: 3096298
                PubMed ID: 21603025
                SO-VID: 3230cff4-cd7e-4fe2-a7f0-7e412ddeb578
                Copyright © Copyright © 2011 Chizuru Akimoto et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 19 October 2010
                Date accepted : 29 January 2011
                Categories
                Subject: Clinical Study

                ScienceOpen disciplines: Neurology
                Data availability:
                ScienceOpen disciplines: Neurology

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