Mitochondrial DNA haplogroups may influence Fabry disease phenotype

Simoncini, Costanza; Chico, Lucia; Concolino, Daniela; Sestito, Simona; Fancellu, Laura; Boadu, William; Sechi, Gian Pietro; Feliciani, Claudio; Gnarra, Maria; Zampetti, Anna; Salviati, Alessandro; Scarpelli, Mauro; Orsucci, Daniele; Bonuccelli, Ubaldo; Siciliano, Gabriele; Mancuso, Michelangelo

doi:10.1016/j.neulet.2016.06.051

Cited by 11 publications

(15 citation statements)

References 27 publications

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“…Although certain haploid groups were shown to be more prevalent in patients, there was no observed correlation with gender, age of onset, or organ involvement [103].…”

Section: Fabry Diseasementioning

confidence: 74%

“…also vary between tissues, thus modulating the phenotype and the natural course of the disease. Although certain haploid groups were shown to be more prevalent in patients, there was no observed correlation with gender, age of onset, or organ involvement [103]. The impaired mitochondrial energy supply in skin fibroblasts from a patient with FD is depicted on Figure 5.…”

Section: Fabry Diseasementioning

confidence: 97%

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Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review

Stępień

Roncaroli

Turton

et al. 2020

JCM

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Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these heterogeneous disorders. Once impaired, dysfunctional mitochondria may impact upon the function of the lysosome by the generation of reactive oxygen species as well as depriving the lysosome of ATP which is required by the V-ATPase proton pump to maintain the acidity of the lumen. Given the reported evidence of mitochondrial dysfunction in LSDs together with the important symbiotic relationship between these two organelles, therapeutic strategies targeting both lysosome and mitochondrial dysfunction may be an important consideration in the treatment of LSDs. In this review we examine the putative mechanisms that may be responsible for mitochondrial dysfunction in reported LSDs which will be supplemented with morphological and clinical information.

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“…Although certain haploid groups were shown to be more prevalent in patients, there was no observed correlation with gender, age of onset, or organ involvement [103].…”

Section: Fabry Diseasementioning

confidence: 74%

Section: Fabry Diseasementioning

confidence: 97%

Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review

Stępień

Roncaroli

Turton

et al. 2020

JCM

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“…Interestingly, urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA, suggesting a possible link between lyso-GB3 and oxidative stress [19]. In 2016, we have also hypothesised that mitochondrial DNA haplogroups may be involved in modulating the oxidative stress in FD, thus explaining the heterogenous expression of FD phenotype [20].…”

Section: Discussionmentioning

confidence: 90%

Oxidative stress biomarkers in Fabry disease: is there a room for them?

et al. 2020

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Background Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. Methods We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. Results AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. Conclusions Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

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“…Although this observation may seem surprising, even monogenic diseases can be substantially influenced by genes capable of modifying disease phenotype [ 30 ]. In fact, this phenomenon was reported also in FD patients for polymorphisms of the genes coding for interleukin 6, endothelial nitric oxide synthase, factor V, protein Z [ 31 ], or those within the mitochondrial genome [ 32 ]. Hence, it appears that low serum bilirubin levels observed in FD patients reflect not only increased oxidative stress but also to a certain extent a genetic predisposition.…”

Section: Discussionmentioning

confidence: 94%

Serum Bilirubin Levels and Promoter Variations in HMOX1 and UGT1A1 Genes in Patients with Fabry Disease

Jirásková

Bortolussi

Dostálová

et al. 2017

Oxidative Medicine and Cellular Longevity

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The aim of our study was to assess the possible relationships among heme oxygenase (HMOX), bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations, serum bilirubin levels, and Fabry disease (FD). The study included 56 patients with FD (M : F ratio = 0.65) and 185 healthy individuals. Complete standard laboratory and clinical work-up was performed on all subjects, together with the determination of total peroxyl radical-scavenging capacity. The (GT)n and (TA)n dinucleotide variations in the HMOX1 and UGT1A1 gene promoters, respectively, were determined by DNA fragment analysis. Compared to controls, patients with FD had substantially lower serum bilirubin levels (12.0 versus 8.85 μmol/L, p = 0.003) and also total antioxidant capacity (p < 0.05), which showed a close positive relationship with serum bilirubin levels (p = 0.067) and the use of enzyme replacement therapy (p = 0.036). There was no association between HMOX1 gene promoter polymorphism and manifestation of FD. However, the presence of the TA7 allele UGT1A1 gene promoter, responsible for higher systemic bilirubin levels, was associated with a twofold lower risk of manifestation of FD (OR = 0.51, 95% CI = 0.27–0.97, p = 0.038). Markedly lower serum bilirubin levels in FD patients seem to be due to bilirubin consumption during increased oxidative stress, although UGT1A1 promoter gene polymorphism may modify the manifestation of FD as well.

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Mitochondrial DNA haplogroups may influence Fabry disease phenotype

Cited by 11 publications

References 27 publications

Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review

Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review

Oxidative stress biomarkers in Fabry disease: is there a room for them?

Serum Bilirubin Levels and Promoter Variations in HMOX1 and UGT1A1 Genes in Patients with Fabry Disease

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