Generation of a human iPSC line from a patient with Leigh syndrome caused by a mutation in the MT-ATP6 gene

Galera-Monge, Teresa; Zurita-Díaz, Francisco; González-Páramos, Cristina; Moreno-Izquierdo, Ana; Fraga, Mario F.; Fernández, Agustín F.; Garesse, Rafael; Gallardo, M. Esther

doi:10.1016/j.scr.2016.04.012

Cited by 16 publications

(17 citation statements)

References 4 publications

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“…The L156R substitution prevents the induction of c-ring rotation (rotation of an oligomeric assembly of c-subunits of the ATP synthase (Kühlbrandt and Davies, 2016)), resulting in decreased ATP synthesis (Uittenbogaard et al, 2018). Heteroplasmy analysis of fibroblasts showed a 92% frequency of this mutation in the cell population, which is consistent with previous reports (Galera-Monge et al, 2016; Iyer et al, 2012; Pastores et al, 1994).…”

Section: Resultssupporting

confidence: 93%

“…The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs), followed by differentiation into specific lineages has become a useful tool for complex disease modeling (Kelava and Lancaster, 2016; Di Lullo and Kriegstein, 2017; Pașca, 2018; Quadrato et al, 2016). In the context of LS, iPSCs have been successfully generated from patients with mutations in mitochondrially encoded ATP Synthase Membrane Subunit 6 (MT-ATP6) (Galera-Monge et al, 2016; Grace et al, 2019; Lorenz et al, 2017; Ma et al, 2015), mitochondrially encoded NADH:Ubiquinone Oxidoreductase Core Subunit 3 (MT-ND3) subunit (Hattori et al, 2016) and the nuclear-encoded gene Surfeit locus protein 1 (SURF1) (Inak et al, 2019, 2021). These iPSC-model systems have been proposed for drug discovery (Inak et al, 2017; Lorenz et al, 2017) as well as testing platforms for potential metabolic rescue treatments (Ma et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Many studies have used LS patient fibroblasts commercially available at the Coriell Institute (Galera-Monge et al, 2016; Hinman et al, 1989; Huh et al, 1990; Iyer et al, 2012; Johnson et al, 2019; Ma et al, 2015; Sorbi and Blass, 1982; Vo et al, 2007; Zheng et al, 2016a). Here we report our findings on the genomic and phenotypic characterization of iPSCs derived from these three LS fibroblast lines.…”

Section: Introductionmentioning

confidence: 99%

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Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Romero-Morales

Rastogi

Temuri

et al. 2020

Preprint

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SummaryLeigh syndrome (LS) is a rare, inherited neuro-metabolic disorder that presents with bilateral brain lesions. This disease is caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated induced pluripotent stem cells (iPSCs) from three widely available LS fibroblast lines and identified, through whole exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS derived cell lines were viable and able to differentiate into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. The DLD-mutant line showed decreased neural rosette (NR) formation, and there were differences in NR lumen area in all three LS lines compared to control. LS-derived cerebral organoids showed defects in neural epithelial bud generation and reduced size when grown for 100 days. Loss of cortical architecture and markers were detected at days 30 and 100. The MT-ATP6/PDH line produced organoid neural progenitor cells with an abnormal mitochondrial morphology characterized by fragmentation and disorganization, and demonstrated increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that could be used as LS model systems.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Romero-Morales

Rastogi

Temuri

et al. 2020

Preprint

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“…Moreover, in another study with MELAS iPSc harboring the same mutation, a higher expression of cardiac markers was detected after spontaneous differentiation of the iPSc with lower mutant mtDNA (Folmes et al, ). Similarly, the LS line L749.1, with almost 100% of the m.8993T>G mutation (Galera‐Monge et al, ), failed to differentiate into CM, suggesting that this event could not be specific for m.13513G>A mutation. Ma et al () also showed an abolished CD in iPSc harboring the mutations m.3243A>G or m.8993T>G in homoplasmy.…”

Section: Discussionmentioning

confidence: 99%

The mutation m.13513G>A impairs cardiac function, favoring a neuroectoderm commitment, in a mutant‐load dependent way

Galera-Monge

Zurita-Díaz

Garesse

et al. 2019

Journal Cellular Physiology

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Mitochondrial disorders (MDs) arise as a result of a respiratory chain dysfunction. While some MDs can affect a single organ, many involve several organs, the brain being the most affected, followed by heart and/or muscle. Many of these diseases are associated with heteroplasmic mutations in the mitochondrial DNA (mtDNA). The proportion of mutated mtDNA must exceed a critical threshold to produce disease. Therefore, understanding how embryonic development determines the heteroplasmy level in each tissue could explain the organ susceptibility and the clinical heterogeneity observed in these patients. In this report, the dynamics of heteroplasmy and the influence in cardiac commitment of the mutational load of the m.13513G>A mutation has been analyzed.This mutation has been reported as a frequent cause of Leigh syndrome (LS) and is commonly associated with cardiac problems. In this report, induced pluripotent stem cell (iPSc) technology has been used to delve into the molecular mechanisms underlying cardiac disease in LS. When mutation m.13513G>A is above a threshold, iPSc-derived cardiomyocytes (iPSc-CMs) could not be obtained due to an inefficient epithelialmesenchymal transition. Surprisingly, these cells are redirected toward neuroectodermal lineages that would give rise to the brain. However, when mutation is below that threshold, dysfunctional CM are generated in a mutant-load dependent way. We suggest that distribution of the m.13513G>A mutation during cardiac differentiation is not at random. We propose a possible explanation of why neuropathology is a frequent feature of MD, but cardiac involvement is not always present.

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“…With iPSCs, some of these problems can be resolved as fibroblast derived from diseased patients could be reprogrammed and potentially differentiated into any cell/tissue to better elucidate the pathological mechanism of a specific mitochondrial disorder on various cells/tissues. Many recent studies have demonstrated the potential for generating human iPSC patient-specific models from LS carrying mutations in MT-ATP6 and MT-ND5 genes ( Galera-Monge et al, 2016 ; Zurita-Diaz et al, 2016 ; Grace et al, 2019 ). Another study combined somatic cell nuclear transfer (SCNT) and iPSC technology to perform a metabolic rescue in the iPSCs generated from these patients, demonstrating the significant possibilities that iPSC models hold, as they could potentially be used to simultaneously study pathogenesis and develop treatments for patients with LS and other mitochondrial diseases ( Ma et al, 2015 ).…”

Section: Disease Models For Lsmentioning

confidence: 99%

Leigh Syndrome: A Tale of Two Genomes

2021

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Leigh syndrome is a rare, complex, and incurable early onset (typically infant or early childhood) mitochondrial disorder with both phenotypic and genetic heterogeneity. The heterogeneous nature of this disorder, based in part on the complexity of mitochondrial genetics, and the significant interactions between the nuclear and mitochondrial genomes has made it particularly challenging to research and develop therapies. This review article discusses some of the advances that have been made in the field to date. While the prognosis is poor with no current substantial treatment options, multiple studies are underway to understand the etiology, pathogenesis, and pathophysiology of Leigh syndrome. With advances in available research tools leading to a better understanding of the mitochondria in health and disease, there is hope for novel treatment options in the future.

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Generation of a human iPSC line from a patient with Leigh syndrome caused by a mutation in the MT-ATP6 gene

Cited by 16 publications

References 4 publications

Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

The mutation m.13513G>A impairs cardiac function, favoring a neuroectoderm commitment, in a mutant‐load dependent way

Leigh Syndrome: A Tale of Two Genomes

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