Generation of three induced pluripotent cell lines (iPSCs) from an Aicardi–Goutières syndrome (AGS) patient harboring a deletion in the genomic locus of the sterile alpha motif and HD domain containing protein 1 (SAMHD1)

Fuchs, Nina V.; Schieck, Maximilian; Neuenkirch, Michaela; Tondera, Christiane; Schmitz, Heike; Wendeburg, Lena; Steinemann, Doris; Elpers, Christiane; Rutsch, Frank; König, Renate

doi:10.1016/j.scr.2019.101697

Cited by 4 publications

(3 citation statements)

References 4 publications

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“…Both variants are absent from GnomAD (https://gnomad.broadinstitute.org/). Truncating variants and intragenic SAMHD1 exon deletions have previously been described as pathogenic (13)(14)(15).…”

Section: Resultsmentioning

confidence: 99%

Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

et al. 2021

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Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic–ischemic injury in some CP cases, several studies suggest that birth asphyxia is actually an uncommon cause, accounting for <10% of CP cases. For children with CP in the absence of traditional risk factors, a genetic basis to their condition is increasingly suspected. Several recent studies indeed confirm copy number variants and single gene mutations with large genetic heterogeneity as an etiology in children with CP. Here, we report three patients with spastic cerebral palsy and a genetically confirmed diagnosis of Aicardi-Goutières syndrome (AGS), with highly variable phenotypes ranging from clinically suggestive to non-specific symptomatology. Our findings suggest that AGS may be a rather common cause of CP, that frequently remains undiagnosed without additional genetic testing, as in only one case a clinical suspicion of AGS was raised. Our data show that a diagnosis of AGS must be considered in cases with spastic CP, even in the absence of characteristic brain abnormalities. Importantly, a genetic diagnosis of AGS may have significant therapeutic consequences, as targeted therapies are being developed for type 1 interferonopathies, the group of diseases to which AGS belongs. Our findings demonstrate the importance of next generation sequencing in CP patients without an identifiable cause, since targeted diagnostic testing is hampered by the often non-specific presentation.

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Section: Resultsmentioning

confidence: 99%

Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

et al. 2021

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“…Approximately, 30% of patients exhibit chilblains-like eruptions, and some cases have also shown the presence of anti-nuclear antibodies, anti-double stranded (ds) DNA antibodies, and manifestations like systemic lupus erythematosus (SLE) [40]. Various research groups have reported the establishment of AGS patient-derived iPS cells with TREX1, RNASEH2B, SAMHD1, and IFIH1 gene mutations [29][30][31][32][33][34][35]. Genova et al established three AGS patient-derived iPS cells and examined the cytotoxicity of several drugs [29].…”

Section: Interferonopathymentioning

confidence: 99%

Investigation of immune-related diseases using patient-derived induced pluripotent stem cells

Shoda,

Natsumoto,

Fujio

2023

Inflamm Regener

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The precise pathogenesis of immune-related diseases remains unclear, and new effective therapeutic choices are required for the induction of remission or cure in these diseases. Basic research utilizing immune-related disease patient-derived induced pluripotent stem (iPS) cells is expected to be a promising platform for elucidating the pathogenesis of the diseases and for drug discovery. Since autoinflammatory diseases are usually monogenic, genetic mutations affect the cell function and patient-derived iPS cells tend to exhibit disease-specific phenotypes. In particular, iPS cell-derived monocytic cells and macrophages can be used for functional experiments, such as inflammatory cytokine production, and are often employed in research on patients with autoinflammatory diseases.On the other hand, the utilization of disease-specific iPS cells is less successful for research on autoimmune diseases. One reason for this is that autoimmune diseases are usually polygenic, which makes it challenging to determine which factors cause the phenotypes of patient-derived iPS cells are caused by. Another reason is that protocols for differentiating some lymphocytes associated with autoimmunity, such as CD4+T cells or B cells, from iPS cells have not been well established. Nevertheless, several groups have reported studies utilizing autoimmune disease patient-derived iPS cells, including patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and systemic sclerosis. Particularly, non-hematopoietic cells, such as fibroblasts and cardiomyocytes, differentiated from autoimmune patient-derived iPS cells have shown promising results for further research into the pathogenesis. Recently, our groups established a method for differentiating dendritic cells that produce interferon-alpha, which can be applied as an SLE pathological model. In summary, patient-derived iPS cells can provide a promising platform for pathological research and new drug discovery in the field of immune-related diseases.

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“…Three isogenic hiPSC clones from a IFIH1 mutated 14 years of age male and proposed as an advanced in vitro model for AGS7 were also developed [ 147 ]. Three induced pluripotent stem cell lines from a patient with a deletion of coding exons 14 and 15 of the SAMHD1 gene were described by Fuchs et al [ 148 ]. All these cell lines ( Table 1 ) will constitute a significant tool to investigate the role of specific mutations in AGS pathogenesis.…”

Section: Astrocytopathies: When Myelin Defects Are Caused By Astrocyte Disfunctionsmentioning

confidence: 99%

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Lanciotti

Brignone

Macioce

et al. 2021

IJMS

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Astrocytes are very versatile cells, endowed with multitasking capacities to ensure brain homeostasis maintenance from brain development to adult life. It has become increasingly evident that astrocytes play a central role in many central nervous system pathologies, not only as regulators of defensive responses against brain insults but also as primary culprits of the disease onset and progression. This is particularly evident in some rare leukodystrophies (LDs) where white matter/myelin deterioration is due to primary astrocyte dysfunctions. Understanding the molecular defects causing these LDs may help clarify astrocyte contribution to myelin formation/maintenance and favor the identification of possible therapeutic targets for LDs and other CNS demyelinating diseases. To date, the pathogenic mechanisms of these LDs are poorly known due to the rarity of the pathological tissue and the failure of the animal models to fully recapitulate the human diseases. Thus, the development of human induced pluripotent stem cells (hiPSC) from patient fibroblasts and their differentiation into astrocytes is a promising approach to overcome these issues. In this review, we discuss the primary role of astrocytes in LD pathogenesis, the experimental models currently available and the advantages, future evolutions, perspectives, and limitations of hiPSC to study pathologies implying astrocyte dysfunctions.

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Generation of three induced pluripotent cell lines (iPSCs) from an Aicardi–Goutières syndrome (AGS) patient harboring a deletion in the genomic locus of the sterile alpha motif and HD domain containing protein 1 (SAMHD1)

Cited by 4 publications

References 4 publications

Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

Investigation of immune-related diseases using patient-derived induced pluripotent stem cells

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

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