Elsevier

Neurobiology of Aging

Volume 33, Issue 5, May 2012, Pages 1017.e17-1017.e23
Neurobiology of Aging

Genetic reports abstract
Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS

https://doi.org/10.1016/j.neurobiolaging.2011.12.003Get rights and content

Abstract

About 5% of amyotrophic lateral sclerosis (ALS) cases are known to be familial (fALS) and mutations in SOD1 and other genes are found in more than 20% of fALS patients and in 2%–4% of apparently sporadic ALS (sALS) cases. However, there are few reports on the proportion of fALS and the frequency of mutations in Korean patients with ALS. We screened mutations in the SOD1, FUS, TARDBP, ANG, and OPTN genes in 258 consecutively enrolled Korean patients with ALS from October 2006 to November 2010. The frequency of fALS was estimated to be 3.5% (9/258), and mutations were identified in 88.9% (8/9) of fALS patients but only in 2.8% (7/249) of sALS patients. Seven fALS and 3 sALS patients had mutations in SOD1 gene while all the others had FUS gene. The proportion of fALS was lower than that reported in Caucasian populations but the frequency of SOD1 gene mutations in Korean fALS patients (77.8%, 7/9) was much higher than that reported in other ethnic groups. These findings might suggest that there is an ethnic difference in the proportion of fALS and the genetic background of ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset, devastating, and untreatable neurodegenerative disorder. ALS is characterized by wasting and weakness of limbs and bulbar and respiratory muscles due to degeneration of motor neurons in the spinal cord, brainstem, and motor cortex, over a time course of approximately 3–5 years from symptom onset. Although most cases of ALS are sporadic (sALS), approximately 5% of ALS patients are known to have familial forms (fALS), often with an autosomal dominant pattern of inheritance (Andersen, 2006, Chiò et al., 2008; Logroscino et al., 2010, Rowland and Shneider, 2001).

To date, a number of genetic loci and disease causing mutations in several genes have been reported to be associated with typical ALS or atypical motor neuron diseases, which are further classified from ALS1 to ALS12 (Ticozzi et al., 2011). Mutations in the Cu/Zn superoxide dismutase 1 gene (SOD1, MIM 147450) are the most common cause of ALS, accounting for about 20% of fALS and less than 1% of sALS cases (Chiò et al., 2008, Rosen et al., 1993). However, the prevalence of SOD1 mutations in both fALS and sALS cases varies because studies have typically been based on case series and specific ethnic groups (Chiò et al., 2008, van Es et al., 2010). Mutations in TARDBP, which encodes the transactive response DNA-binding protein 43 (TDP-43), are responsible for approximately 5% of ALS cases (Corrado et al., 2010, Kabashi et al., 2008, Van Deerlin et al., 2008). Recently, mutations in FUS, which also encodes the DNA/RNA binding protein, were found in approximately 5% of patients with ALS who tested negative for SOD1 and TARDBP mutations (Kwiatkowski et al., 2009, Vance et al., 2009). Pathogenic mutations in other genes have also been identified and account for < 5% of ALS cases (Greenway et al., 2006, Maruyama et al., 2010).

Although many studies have been performed to estimate the proportion of fALS and the frequency of mutations in fALS and sALS patients in various populations, there are currently no data in Korean patients with ALS. In the present study, we sought to estimate the proportion of fALS in a consecutive series of ALS patients and to investigate the mutational frequencies and spectrums of SOD1, TARDBP, FUS, ANG, and OPTN genes.

Section snippets

Subjects

A consecutive series of ALS patients from the ALS Clinic in the Neurology Department at Hanyang University Hospital in Seoul, Korea were prospectively enrolled from October 2006 to November 2010. All patients were of Korean descent. All subjects were selected according to revised El Escorial criteria, fulfilling the criteria for probable or definite ALS (Brooks et al., 2000). ALS patients were classified as familial when they had at least 1 family member in the same pedigree that was reported

Clinical findings

A total of 258 consecutive ALS patients were included in this study. The clinical findings are summarized in Table 1. Of the 258 patients, 164 were male and 94 were female (male:female ratio of 1.7:1.0) and the mean age of onset was 53.4 ± 11.5 years (range, 25–81 years). There were 36 patients with ages of onset younger than 40 years. In male patients, the mean onset age was 52.9 years, similar to females (54.3 years; p = 0.358). Nine ALS patients (9/258; 3.5%) had family histories of ALS

Discussion

In this study, which included a detailed genetic analysis of the SOD1, FUS, TARDBP, OPTN, and ANG genes from 9 fALS index patients and 249 sALS patients, we identified fifteen mutations in 8 fALS and 7 sALS patients, including 9 SOD1 mutations in 10 patients and 5 FUS mutations in 5 patients. No mutations or novel variants in OPTN, TARDBP, and ANG were identified in this cohort, which is consistent with previous findings (Cronin et al., 2008, Guerreiro et al., 2008, Sugihara et al., 2011).

Disclosure statement

The authors disclose no conflicts of interest.

Acknowledgements

This study was supported by a grant from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A101712), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2010-0004450) and a grant from IN-SUNG Foundation for Medical Research.

References (47)

  • T. Aguirre et al.

    Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium

    Eur. J. Hum. Genet.

    (1999)
  • P.M. Andersen

    Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene

    Curr. Neurol. Neurosci. Rep.

    (2006)
  • P.M. Andersen et al.

    Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia

    Brain

    (1997)
  • P.M. Andersen et al.

    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 Mot. Neuron Disord.

    (2003)
  • B.R. Brooks et al.

    El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis

    Amyotroph. Lateral Scler. Other Mot. Neuron Disord.

    (2000)
  • S. Byrne et al.

    Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis

    J. Neurol. Neurosurg. Psychiatry.

    (2011)
  • A. Chiò et al.

    Prevalence of SOD1 mutations in the Italian ALS population

    Neurology

    (2008)
  • L. Corrado et al.

    Mutations of FUS gene in sporadic amyotrophic lateral sclerosis

    J. Med. Genet.

    (2010)
  • S. Cronin et al.

    Screening of hypoxia-inducible genes in sporadic ALS

    Amyotroph. Lateral Scler.

    (2008)
  • M.E. Cudkowicz et al.

    Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis

    Ann. Neurol.

    (1997)
  • A. Eisen et al.

    SOD1 gene mutations in ALS patients from British Columbia, Canada: clinical features, neurophysiology and ethical issues in management

    Amyotroph. Lateral Scler.

    (2008)
  • R. Fernández-Santiago et al.

    Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis

    J. Neurol.

    (2009)
  • M.J. Greenway et al.

    ANG mutations segregate with familial and “sporadic” amyotrophic lateral sclerosis

    Nat. Genet.

    (2006)
  • Cited by (18)

    • Genetic and clinical characteristics of ALS patients with NEK1 gene variants

      2023, Neurobiology of Aging
      Citation Excerpt :

      Among them, Case No. 1937 carried the NEK1 missense variant (p.Leu55Val), which was considered PP, and also carried CHMP2B (p.Arg32*) and TBK1 (p.Cys91*) variants, of which the pathogenicity of CHMP2B p.Arg32* variant is uncertain, and TBK1 p.Cys91* variant is considered to be pathogenic, therefore, the clinical manifestations in this patient may be a combination of multiple genes. Case No. 1994, in addition to carrying the NEK1 missense variant (p.Leu996Val), which was considered benign in our study, also carried the FUS (p.Arg495*) variant that has been reported in many studies previously(Kwon et al., 2012, van Blitterswijk et al., 2012, Waibel et al., 2010, Yan et al., 2010, ), and its pathogenicity was confirmed. Therefore, FUS is the main causative gene for this patient.

    • De novo FUS mutations in 2 Korean patients with sporadic amyotrophic lateral sclerosis

      2015, Neurobiology of Aging
      Citation Excerpt :

      Here, we report the presence of de novoFUS gene mutations in 2 Korean sALS patients. We screened mutations in 5 ALS genes including SOD1 and FUS in 258 Korean ALS patients and found FUS mutations in 4 sALS patients (Kwon et al., 2012). Among them, 2 sALS patients with living parents were ascertained to have variants in the FUS gene, HS-197 with p.Arg495* and HS-131 with p.Gly504Trpfs*12.

    • De novo FUS gene mutations are associated with juvenile-onset sporadic amyotrophic lateral sclerosis in China

      2013, Neurobiology of Aging
      Citation Excerpt :

      Therefore, in SALS, the frequency of FUS mutations in the Chinese population (1.5%, 95% confidence interval [CI], 0.2%–2.9%) is similar to the Korean population (4/249; 1.6%; 95% CI, 0%–3.2%) (Kwon et al., 2012) but higher than among Caucasians (0.6%; 95% CI, 0.4%–0.8%), whereas in FALS, the frequency in the Chinese population (11.4%; 95% CI, 0.9%–22.0%) is higher than in the Japanese (4/40; 10%; 95% CI, 0.7%–19.3%) (Suzuki et al., 2010) and Caucasian (4.9%; 95% CI, 3.9%–6.0%) populations. Combining results from all the previous studies (Baumer et al., 2010; Belzil et al., 2009, 2011a, 2011b, 2012; Blair et al., 2010; Broustal et al., 2010; Brown et al., 2012; Chio et al., 2009; Corrado et al., 2010; Damme et al., 2010; DeJesus-Hernandez et al., 2010; Drepper et al., 2011; Groen et al., 2010; Hewitt et al., 2010; Huang et al., 2010; Ito et al., 2011b; Kwiatkowski et al., 2009; Kwon et al., 2012; Lai et al., 2011; Millecamps et al., 2010; Rademakers et al., 2010; Robertson et al., 2011; Rutherford et al., 2012; Sproviero et al., 2012; Suzuki et al., 2010; Syriani et al., 2011; Tateishi et al., 2010; Ticozzi et al., 2009; Tsai et al., 2011; Vance et al., 2009; Waibel et al., 2010; Yamamoto-Watanabe et al., 2010; Yamashita et al., 2011; Yan et al., 2010; Zou et al., 2012a) and our present study, 54 different pathogenic FUS mutations have been identified in both FALS and SALS patients (Supplementary Table 1, Fig. 1), 97 FUS mutation carriers have been identified among 2167 non-SOD1, non-TARDBP FALS probands, and 48 mutation carriers have been identified among 7389 SALS patients (Supplementary Table 1). The prevalence of FUS mutations in SOD1- and TARDBP-negative FALS (4.5%) (approximately 6.0% for all FALS; 95% CI, 4.8%–7.1%) and SALS (0.6%; 95% CI, 0.5%–0.8%) makes FUS mutation the fourth most common cause of ALS after C9orf72, SOD1, and TARDBP mutations (Zou et al., 2012b).

    View all citing articles on Scopus
    1

    Contributed equally to this work.

    View full text