Genetic analysis of the SOD1 and C9ORF72 genes in Hungarian patients with amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons. To date, more than 20 genes have been implicated in ALS, and of these, the 2 most frequently mutated are the superoxide dismutase 1 (SOD1) gene and the chromosome 9 open reading frame 72 (C9ORF72) gene. In this study, we aimed to investigate the contribution of these 2 Mendelian genes to the development of the disease in Hungarian ALS patients (n = 66). Direct sequencing of the SOD1 gene revealed a novel (p.Lys91ArgfsTer8) and 3 recurrent heterozygous mutations (p.Val14Met, p.Asp90Ala, and p.Leu144Phe) in 5 patients. The novel p.Lys91ArgfsTer8 mutation led to a frameshift causing the addition of 8 new amino acids, including a premature stop codon at position 99. The GGGGCC hexanucleotide repeat expansion of the C9ORF72 gene was present in 1 ALS patient. This study represents the first genetic analysis of 2 major ALS causative genes in a cohort of Hungarian ALS patients and contributes to the further understanding of the genetic and phenotypic diversity of ALS.

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

“…Since the discovery of its association with ALS in 1993, more than 180 SOD1 mutations have been described (Pasinelli and Brown, 2006; Tripolszki et al, 2017). SOD1 encodes a ubiquitously expressed cytosolic enzyme with a molecular mass of 32 kDa (Nithya et al, 2016), and its normal cellular function is to detoxify the endogenously produced superoxide, by converting it to oxygen and hydrogen peroxide (Sakurai et al, 2014).…”

Angiogenin mutations in Hungarian patients with amyotrophic lateral sclerosis: Clinical, genetic, computational, and functional analyses

“…The known M‐24I mutation (c.3G>T) was detected in two patients. One of the patients, who was described in our previous study (Tripolszki et al., ), also carried a mutation in the SOD1 gene (V14M).…”

“…One of the patients with the ANG M‐24I also carried a mutation in the SOD1 gene (V14M) and was described in our previous study (Tripolszki et al., ). The co‐occurrence of different variants in ALS‐associated genes was also detected in other ALS cohort screenings (Kenna et al., ; Krüger et al., ).…”

“…The aim of this study was to evaluate the contribution of mutations in ANG , a major ALS gene, to the pathogenesis of the disease in Hungarian patients. The patients positive for SOD1 or C9orf72 repeat expansion identified in our previous study (Tripolszki et al., ) were not excluded, as there is evidence that ALS is oligogenic (van Blitterswijk et al., ). To explore the underlying mechanisms that result in loss of function of the detected R33W mutant protein, computational simulations, ribonucleolytic assays, and nuclear translocation assays were performed.…”

“…In the past decades, more than 30 genes involved in the etiology of the disease have been identified (Amyotrophic Lateral Sclerosis Online Genetics Database, ALSoD; Abel, Powell, Andersen, & Al-Chalabi, 2012). The prevalence of mutations of the two most frequently mutated genes, SOD1 and C9orf72 repeat expansion was previously reported for the Hungarian population (Tripolszki et al, 2017).…”