Dystrophin Deficiency Leads to Genomic Instability in Human Pluripotent Stem Cells via NO Synthase-Induced Oxidative Stress

Jelínková, Šárka; Fojtík, Petr; Kohutova, Aneta; Vilotić, Aleksandra; Marková, Lenka; Pešl, Martin; Juráková, Tereza; Krutá, Miriama; Vrbský, Jan; Gaillyová, Renata; Valášková, Iveta; Frák, Ivan; Lacampagne, Alain; Forte, Giancarlo; Dvořák, Petr; Méli, Albano C.; Rotrekl, Vladimír

doi:10.3390/cells8010053

Cited by 32 publications

(28 citation statements)

References 96 publications

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“…This frequency is identical to that of more well know tumor suppressor genes in breast cancer, PTEN and ARID1A. In induced pluripotent stem cells, loss of dystrophin leads to genomic instability 57 .…”

Section: Somatic Mutationssupporting

confidence: 63%

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

Zeng¹,

et al. 2019

Preprint

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One Sentence Summary: Genetic aberrations in benign breast lesions distinguish breast cancer cases from controls and predict cancer risk.Abstract: It is largely unknown how the risk of development of breast cancer is transduced by somatic genetic alterations. To address this lacuna of knowledge and acknowledging that benign breast disease (BBD) is an established risk factor for breast cancer, we established a case-control study: The Benign Breast & Cancer Risk (BBCAR) Study. Cases are women with BBD who developed subsequent invasive breast cancer (IBC) at least 3 years after the biopsy and controls are women with BBD who did not develop IBC (median follow-up 16.6 years). We selected 135 cases and individually matched controls (1:2) to cases based on age and type of benign disease: non-proliferative or proliferation without atypia. Whole exome sequencing was performed on DNA from the benign lesions and from subsets with available germline DNA or tumor DNA. Although the number of cases and controls with copy number variation data is limited, several amplifications and deletions are exclusive to the cases. In addition to two known mutational signatures, a novel signature was identified that is significantly (p=0.007) associated with triple negative breast cancer. The somatic mutation rate in benign lesions is similar to that of invasive breast cancer and does not differ between cases and controls. Two mutated genes are significantly associated with time to the diagnosis of breast cancer, and mutations shared between the benign biopsy tissue and the breast malignancy for the ten cases for which we had matched pairs were identified. BBD tissue is a rich source of clues to breast oncogenesis.

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Section: Somatic Mutationssupporting

confidence: 63%

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

Zeng¹,

et al. 2019

Preprint

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“…All human pluripotent stem cell (hPSC) lines were routinely maintained on feeder layer of mitotically inactivated mouse embryonic fibroblasts (mEF) as previously described (Dvorak et al, 2005;Krutá et al, 2014;Jelinkova et al, 2019a).…”

Section: Cell Lines Cultivation Reprogramming and Hpsc Differentiamentioning

confidence: 99%

DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology

Jelínková

Vilotić

Přibyl

et al. 2020

Front. Bioeng. Biotechnol.

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Duchenne muscular dystrophy (DMD) is associated with progressive dilated cardiomyopathy eventually leading to heart failure as the main cause of death in DMD patients. A human cardiomyocyte (CM) model was developed from several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and hESC line with deletion of DMD gene generated by CRISPR/Cas9 technology. DMD hPSC were differentiated into CMs. DMD mutation-carrying cells are less prone to differentiate into CMs. DMD CMs further demonstrate an enhanced cell death rate. Ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (DHPR overexpression). DMD-CMs exhibited mishandling of calcium demonstrated by increased time of calcium release. Further mechanical impairment (hypocontractility), bradycardia, increased beat rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors' expression was found in DMD-CMs (LTCC L-type calcium channel, cTnT-cardiac troponin T, Kir2.1-potassium channel).

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“…The dystrophin glycoprotein complex also includes the nitric oxide synthase (NOS) [54], an enzyme that catalyzes the production of nitric oxide from l-arginine. A dysfunction of NOS also causes OS in Duchenne muscular dystrophy [55]. In the case of dysferlinopathy, as shown in Figure 5, dysferlin deficiency results in impaired membrane repair [6], and de novo expression of non-selective channels, such as connexin-based hemichannels, P2X7 receptors and transient receptor potential TRPV2 channels [56], which might contribute to an altered Ca 2+ homeostasis, mitochondrial dysfunction [12] and ROS production [13].…”

Section: Comparison Of the Effect Of Nac In Bla/j And MDX Micementioning

confidence: 99%

N-Acetylcysteine Reduces Skeletal Muscles Oxidative Stress and Improves Grip Strength in Dysferlin-Deficient Bla/J Mice

García-Campos

Báez‐Matus

Paz-Araos

et al. 2020

IJMS

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Dysferlinopathy is an autosomal recessive muscular dystrophy resulting from mutations in the dysferlin gene. Absence of dysferlin in the sarcolemma and progressive muscle wasting are hallmarks of this disease. Signs of oxidative stress have been observed in skeletal muscles of dysferlinopathy patients, as well as in dysferlin-deficient mice. However, the contribution of the redox imbalance to this pathology and the efficacy of antioxidant therapy remain unclear. Here, we evaluated the effect of 10 weeks diet supplementation with the antioxidant agent N-acetylcysteine (NAC, 1%) on measurements of oxidative damage, antioxidant enzymes, grip strength and body mass in 6 months-old dysferlin-deficient Bla/J mice and wild-type (WT) C57 BL/6 mice. We found that quadriceps and gastrocnemius muscles of Bla/J mice exhibit high levels of lipid peroxidation, protein carbonyls and superoxide dismutase and catalase activities, which were significantly reduced by NAC supplementation. By using the Kondziela’s inverted screen test, we further demonstrated that NAC improved grip strength in dysferlin deficient animals, as compared with non-treated Bla/J mice, without affecting body mass. Together, these results indicate that this antioxidant agent improves skeletal muscle oxidative balance, as well as muscle strength and/or resistance to fatigue in dysferlin-deficient animals.

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Dystrophin Deficiency Leads to Genomic Instability in Human Pluripotent Stem Cells via NO Synthase-Induced Oxidative Stress

Cited by 32 publications

References 96 publications

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology

N-Acetylcysteine Reduces Skeletal Muscles Oxidative Stress and Improves Grip Strength in Dysferlin-Deficient Bla/J Mice

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