Generation of human induced pluripotent stem cell lines from 2 patients with MIRAGE syndrome

Fischer, Iris; Küchler, Judit; Schaar, Claudia; Fisch, Tanja; Cernoch, Janine; Fischer, Kristin; Vallone, Valeria Fernández; Kühnen, Peter; Stachelscheid, Harald

doi:10.1016/j.scr.2021.102417

Cited by 4 publications

(4 citation statements)

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“…Indeed, induced pluripotent stem cell lines (iPSC) have been generated from fibroblasts from two MIRAGE patients. 2,24 These represent a potentially important resource to further investigate the disease mechanisms of MIRAGE syndrome and model the underlying molecular basis, at least in vitro. Understanding the molecular function of SAMD9 is extremely important to help us develop personalised management and effective therapies for individuals with SAMD9-associated variants.…”

Section: Discussionmentioning

confidence: 99%

Investigating ultrastructural morphology in MIRAGE syndrome (SAMD9)-derived fibroblasts using transmission electron microscopy.

et al. 2023

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Background: Heterozygous de novo variants in the gene SAMD9 cause the complex multisystem disorder, MIRAGE syndrome. Patients are characterised by myelodysplasia, infections, growth restriction, adrenal insufficiency, gonadal dysfunction and enteropathies. Pathogenic variants in SAMD9 are gain-of-function and enhance its role as a growth repressor, leading to growth restriction of many tissues. Two studies have reported changes in skin fibroblasts derived from MIRAGE patients, more specifically identifying enlarged endosomes. We have also previously shown subtle changes in endosome size in patients’ fibroblasts compared to controls. However, these variations in endosomes were not as marked as those described in the literature. Methods: We have performed an observational study using transmission electron microscopy (EM) in a larger number of cells derived from three patients’ fibroblasts to assess ultrastructure morphology compared to control images. Results: Consistent changes were observed in cell organelles in all patient samples. In particular, increased endosomal activity was detected, characterised by augmented pinocytosis and vesicle budding, increased endosome number, as well as by large lysosomes and endosomes. Endoplasmic reticulum was also prominent. Mitochondria appeared enlarged in selected cells, possibly due to cellular stress. Cell nuclei did not display major differences compared to controls. Conclusions: EM is a powerful tool to investigate morphological features of tissues and cell organelles, although EM data could be affected by sample preparation methodology, therefore potentially explaining the variability between independent studies, and its analysis can be dependent on the experience of the researcher. The increased endosomal activity we have observed in patients’ fibroblasts could indicate that SAMD9 regulates endocytosis of receptors, acting as an endosome fusion facilitator, or in lysosomal activation. However, the precise mechanism(s) by which SAMD9 regulates cell growth is still not fully understood, and further studies are needed to elucidate its pathogenic pathway and develop therapeutic approaches to support patients.

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Section: Discussionmentioning

confidence: 99%

Investigating ultrastructural morphology in MIRAGE syndrome (SAMD9)-derived fibroblasts using transmission electron microscopy.

et al. 2023

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“…32 Clarification of the tissue/organ-level pathogenesis of MIRAGE syndrome will require not only further analysis of patient-derived materials but also analyses of genetically engineered animal models 27 and patient-derived iPS cells. 33 Third, understanding of the phenotypic spectrum of SAMD9 variant carriers remains still incomplete. Sahoo et al have shown that a significant proportion of the SAMD9 variant carriers present only with MDS.…”

Section: Future Directionsmentioning

confidence: 99%

“…The precise mechanism of immunodeficiency, which is directly related to prognosis, is poorly understood, although a recent study using flow cytometric analysis of patients' peripheral leukocytes revealed characteristic loss of circulating dendritic cells 32 . Clarification of the tissue/organ‐level pathogenesis of MIRAGE syndrome will require not only further analysis of patient‐derived materials but also analyses of genetically engineered animal models 27 and patient‐derived iPS cells 33 …”

Section: Future Directionsmentioning

confidence: 99%

Discovery of MIRAGE syndrome

Narumi

2022

Pediatrics International

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Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel single-gene disorder discovered through whole-exome sequencing for pediatric patients with adrenal insufficiency of unknown etiology, and is caused by de novo heterozygous variants in SAMD9. MIRAGE syndrome was initially discovered as a systemic disease affecting multiple systems, including hematopoietic, immune, endocrine, and gastrointestinal systems but later studies revealed a subset of patients with myelodysplastic syndrome as the sole manifestation. In addition, pathogenic variants in SAMD9L, a paralog gene of SAMD9, were reported to cause an inherited disorder of the hematopoietic system and central nervous system, called ataxia-pancytopenia syndrome. This article reviews the history of MIRAGE syndrome from its discovery to the proposal of SAMD9/SAMD9L syndromes, and discusses directions for future research.

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“…Mutations in SAMD9 (sterile α motif domain-containing protein 9) are usually recognized early in life, as adaptive immune response impairment leads to chronic childhood infections and high mortality by age 10. 1 2 SAMD9 maps to chromosome 7q21.2, a region frequently deleted in myeloid malignancies. Narumi et al 3 were the first to implicate germline missense SAMD9 mutations as causative for a rare condition known as MIRAGE syndrome (i.e., myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital anomaly, and enteropathy).…”

Section: Introductionmentioning

confidence: 99%

Phenotype from SAMD9 Mutation at 7p21.2 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1

Sills

Wood

2021

Glob Med Genet

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Sterile α motif domain-containing protein 9 (SAMD9) is a regulatory protein centrally involved in cell proliferation and apoptosis. Mapped to 7p21.1, variants in SAMD9 have been reported in <50 pediatric cases worldwide, typically with early lethality. Germline gain-of-function SAMD9 variants are associated with MIRAGE syndrome (myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital anomalies, and enteropathy). Spalt like transcription factor 1 (SALL1) is a zinc finger transcriptional repressor located at 16q12.1 where only two transcript variants in SALL1 are known. RUNX2 (6p21.1) encodes a nuclear protein with a Runt DNA-binding domain critical for osteoblastic differentiation, skeletal morphogenesis, and serves as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. RUNX2 and SALL1 are thus both “master regulators” of tissue organization and embryo development. Here, we describe exome sequencing and copy number variants in two previously unknown mutations—R824Q in SAMD9, and Q253H in SALL1. A multiexon 3′ terminal duplication of RUNX2 not previously encountered is also reported. This is the first known phenotype assessment for an intersection of all three variants in a healthy 46,XX adult. Focusing on developmental progress, ultrastructural renal anatomy, and selected reproductive aspects, we describe this unique genotype diagnosed incidentally during coronavirus disease 2019 (COVID-19) illness. Individually, disruption in SAMD9, RUNX2, or SALL1 would be expected to give a bleak prognosis. However, this variant convergence appears to dampen severe pathology perhaps by cross-gene silencing of effects normally deleterious when such changes occur alone.

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Generation of human induced pluripotent stem cell lines from 2 patients with MIRAGE syndrome

Cited by 4 publications

References 4 publications

Investigating ultrastructural morphology in MIRAGE syndrome (SAMD9)-derived fibroblasts using transmission electron microscopy.

Investigating ultrastructural morphology in MIRAGE syndrome (SAMD9)-derived fibroblasts using transmission electron microscopy.

Discovery of MIRAGE syndrome

Phenotype from SAMD9 Mutation at 7p21.2 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1

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