Phenotypic Heterogeneity in a SOD1 G93D Italian ALS Family: An Example of Human Model to Study a Complex Disease

Department of Laboratory Medicine, Medical Genetics, Niguarda Ca' Granda Hospital, Milan, Italy.
Journal of Molecular Neuroscience (Impact Factor: 2.34). 12/2010; 44(1):25-30. DOI: 10.1007/s12031-010-9480-4
Source: PubMed


We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.

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    • "However, further investigation is required to assess a possible relationship between metal imbalance and the many biosynthetic steps leading to functional metalloproteins, as well as the molecular basis of mid-to long-term effects of metal imbalance on the energy status and the redox balance of neuronal cells. Effects on other proteins involved in metal homeostasis within the cytoplasm or in specific cellular compartments (such as metallothioneins or ferritin[35,38,41]) and on proteins involved in controlling the intracellular redox potential and/or the concentration of active chemical species (such as peroxides and superoxides[19]) also remain to be assessed. "
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) has often been associated with improper/altered metal metabolism. Analysis of thiophylic metals in serum from a small and geographically restricted cohort of ALS patients indicates contents of Pb and Ni much higher in patients than in controls (Ni, 5-fold; Pb, 2-fold). Se levels are also higher in the patients’ group, which has instead lower As levels than controls. Thiophylic metals may impair biogenesis of FeS clusters or substitute for iron, even in folded proteins; Se may non-functionally replace S. Thus, improper assembly/ function of FeS proteins could represent another possible issue to be considered in ALS pathogenesis.
    Full-text · Article · Jan 2016
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    • "The aim of the present study was to verify whether the 50 bp deletion polymorphism correlated, in vivo, with varied SOD1 mRNA expression and with consequent phenotypic heterogeneity in an Italian SALS population. Indeed, epidemiological researches reported phenotype variations in age and site of onset, disease duration and also symptomatology in both familial and sporadic ALS, which may reflect the effect of mRNA modulation caused by inter-individual genetic differences [13] [14] [15]. "
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    ABSTRACT: The genetic association between homozygosity for a 50 bp deletion polymorphism in the SOD1 promoter, 1684 bp upstream of the ATG, and an increased age of symptom onset was observed in various populations of ALS patients. Moreover, it has been demonstrated that this deletion reduces SOD1 expression in vitro. The objective of the present study was to test whether the observed association is replicated in patients from an Italian population and to check whether the deletion correlates with reduced SOD1 mRNA expression in vivo. Genomic DNA from 235 Italian SALS cases and 245 age- and sex-matched donors from the same ethnic background was screened for the 50 bp SOD1 promoter deletion by real time PCR assays. No differences were observed between ALS patients and controls for the frequency of both the alleles (D=deleted, N=non-deleted; p=0.95) and genotypes (p=0.90). Furthermore, stratification of the ALS samples showed that this variation was not associated with increased age of onset in ND and DD patients in comparison to NN patients (p=0.48). Finally, we performed real-time RT-PCR to quantify SOD1 mRNA levels in 48 patients and we did not find a relevant difference among the three sub-groups of genotypes (p=0.30). Our data suggest that the studied polymorphism does not modulate SOD1 mRNA level and disease phenotype in an Italian population.
    Full-text · Article · Feb 2012 · Journal of the neurological sciences
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    • "No mutation was found in patient ZM. Our findings confirm the hypothesis that variants of ANG gene may influence clinical manifestations in patients bearing SOD1 mutation (Penco et al., 2011). ANG mutations were recently reported in 2 patients harboring FUS mutations , but the possible effect on phenotypic variability was not investigated (Millecamps et al., 2010). "
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    ABSTRACT: SOD1 G93D mutation has been described in amyotrophic lateral sclerosis (ALS) patients with slowly progressive disease. We describe an Italian patient affected by sporadic ALS with the SOD1 G93D mutation that disclosed an unusual rapid progression with death occurring after 30 months from the symptom onset. Considering the atypical clinical course further genes associated with ALS or known to be causative were studied including ANG, PGRN, TARDBP, FUS, VCP, CHRNA3, CHRNA4, and CHRNB4. A novel heterozygous ANG missense variant (c.433 C>T, p.R145C) was identified which is neither reported in controls nor in 1000 genomes and single nucleotide polymorphism (SNP) databases. This report confirms that clinical course of SOD1-related ALS may be modulated by other causative or associated genes, including ANG and suggests that extensive screening of ALS-associated genes in patients with an already identified mutation may be helpful for better knowledge of genetic architecture of ALS.
    Full-text · Article · May 2011 · Neurobiology of aging
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