Mitochondrial DNA pathogenic mutations in multiple symmetric lipomatosis

López‐Gallardo, Ester; Cammarata‐Scalisi, Francisco; Emperador, Sonia; Hernández-Ainsa, Carmen; Habbane, Mouna; Vela-Sebastián, Ana; Bayona‐Bafaluy, M. Pilar; Montoya, Julio; Ruiz‐Pesini, Eduardo

doi:10.1111/cge.13701

Cited by 8 publications

(6 citation statements)

References 23 publications

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“…From a histological point of view, the adipose tissue of all patients was characterized by smaller adipocytes and by the presence of fibrotic and vascular enhancement but without atypia characteristic of lipomas [3]. Moreover, tissues were assessed for the presence of m.8363G > A and m.8344A > G, two mitochondrial DNA mutations reported as present in some MD patients [34,35]. None of the patients carried either of the two mutations taken in consideration.…”

Section: Discussionmentioning

confidence: 99%

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

Caponnetto

Manini

Bulfoni

et al. 2020

Cells

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Madelung Disease (MD) is a syndrome characterized by the accumulation of aberrant symmetric adipose tissue deposits. The etiology of this disease is yet to be elucidated, even though the presence of comorbidities, either genetic or environmental, has been reported. For this reason, establishing an in vitro model for MD is considered crucial to get insights into its physiopathology. We previously established a protocol for isolation and culture of stem cells from diseased tissues. Therefore, we isolated human adipose-derived stem cells (ASC) from MD patients and compared these cells with those isolated from healthy subjects in terms of surface phenotype, growth kinetic, adipogenic differentiation potential, and molecular alterations. Moreover, we evaluated the ability of the MD-ASC secretome to affect healthy ASC. The results reported a difference in the growth kinetic and surface markers of MD-ASC compared to healthy ASC but not in adipogenic differentiation. The most commonly described mitochondrial mutations were not observed. Still, MD-ASC secretome was able to shift the healthy ASC phenotype to an MD phenotype. This work provides evidence of the possibility of exploiting a patient-based in vitro model for better understanding MD pathophysiology, possibly favoring the development of novel target therapies.

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Section: Discussionmentioning

confidence: 99%

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

Caponnetto

Manini

Bulfoni

et al. 2020

Cells

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“…Although familial cases of MSL have been described, the genetic alterations causing the disease are still unknown. Both autosomic dominant and recessive inheritance have been hypothesized and variations in mitochondrial DNA (mtDNA) or MFNT2, a gene involved in mitochondrial fusion associated with other syndromes or complex diseases, were identified in some MSL cases [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

White Adipose Tissue Expansion in Multiple Symmetric Lipomatosis Is Associated with Upregulation of CK2, AKT and ERK1/2

Sanna

Borgo

Compagnin

et al. 2020

IJMS

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Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by overgrowing lipomatous tissue (LT) in the subcutaneous adipose tissue (SAT). What LT is and how it expands are not completely understood; previous data suggested that it could derive from brown AT precursors. In six MSL type I patients, we compared LT morphology by histological and immunohistochemistry (IHC) analysis, gene expression, by qPCR, kinase activity, by Western Blot and in vitro assay to paired-control SAT using AT from patients with pheochromocytoma as a human browning reference. In the stromal vascular fraction (SVF), we quantified adipose stem cells (ASCs) by flow cytometry, the proliferation rate, white and beige adipogenic potential and clonogenicity and adipogenicity by a limiting dilution assay. LT displayed white AT morphology and expression pattern and did not show increased levels of the brown-specific marker UCP1. In LT, we evidenced AKT, CK2 and ERK1/2 hyperactivation. LT-SVF contained increased ASCs, proliferated faster, sprouted clones and differentiated into adipocytes better than the control, displaying enhanced white adipogenic potential but not increased browning compared to SAT. In conclusion, LT is a white AT depot expanding by hyperplasia through increased stemness and enhanced white adipogenesis upregulating AKT, CK2 and ERK1/2, which could represent new targets to counteract MSL.

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“…13,14 Molecularly, gene mutation or deletion was associated with MSL development. For example, mtDNA (m.A8344G, m.G8363A, or m.T8357C) mutations of the tRNALys or single mtDNA deletions in MSL patients 7,9,[15][16][17][18] and the latter gene mutations resulted in a clinical characterization of myoclonus epilepsy associated with ragged-red fibers (MERRF) syndrome. 17 In contrast, gene mutations or deletions of the nonmitochondrial genes, including mitofusin-2 (MFN2), Lipase E, Hormone Sensitive Type (LIPE) and Calcyphosine Like (CAPSL), were also reported in familial MSL.…”

Section: Introductionmentioning

confidence: 99%

“…17,19,20 In addition, alcohol could lead to mitochondrial or β-adrenoceptor dysfunction and result in altered mitochondrial function and loss of or reduced lipolysis. 11,15 The adipose tissue lipoma-like mass (ATLLM) specimens obtained from MSL patients showed multilocular and small adipocytes or were rich in fibrous and vascular tissues compared with the normal subcutaneous adipose tissues (SATs). 11,16,19 Human adipose tissue-derived mesenchymal stromal cells (hADSCs) isolated from MSL adipose tissues expressed a high level of uncoupling protein 1 (UCP-1), a marker of brown adipose tissues, and even higher UCP-1 levels after noradrenaline stimulation.…”

Section: Introductionmentioning

confidence: 99%

<p>Cbl Proto-Oncogene B (CBLB) c.197A>T Mutation Induces Mild Metabolic Dysfunction in Partial Type I Multiple Symmetric Lipomatosis (MSL)</p>

Chen

Wan

Zhao

et al. 2020

DMSO

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Background: Multiple symmetric lipomatosis (MSL) is a rare disease showing chronic progression of multiple, symmetrical, and non-encapsulated subcutaneous lipoma. The cause of the disease remains unknown. Patients and Methods: This study reported and summarized 13 sporadic cases of Type I MSL patients in terms of histopathology and cellular and molecular biology and assessed the CBLB c.197A>T mutation in the IRS1-PI3K-Akt pathway. Results: The clinical data showed that these 13 Type I patients were all male with a mean age of 57.0 ± 6.6 years old and consumed alcohol heavily. The laboratory tests revealed that most of the patients had hyperuricemia, diabetes, hyperinsulinemia, or insulin resistance; however, their blood lipid levels were close to a normal range. The imaging data exhibited lipomas that only occurred subcutaneously but not viscerally, ie, Types Ia (15.4%), Ib (30.8%), and Ic (53.8%). The molecular analyses of adipocytes of isoprenaline stimulated human adipose tissue-derived mesenchymal stromal cells (hADSCs) isolated from the adipose tissue lipoma-like masses (ATLLM) demonstrated that these adipocytes did not express UCP-1. The Cbl proto-oncogene B (CBLB), an E3 ubiquitin-protein ligase, was associated with insulin resistance and obesity and was mutated (ie, CBLB c.197A>T) in four MSL patients after the whole genome and Sanger sequencing of the blood samples. Furthermore, the CBLB c.197A>T mutation induced hADSC resistance to insulin by inactivation of the IRS-1-PI3K-AKT pathway. Conclusion: This study analyzed clinical, histopathological, and cellular and molecular biological characterizations of 13 Type I MSL patients and identified the CBLB c.197A>T heterozygous mutation that could be responsible for MSL metabolic dysfunction or even MSL development.

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Mitochondrial DNA pathogenic mutations in multiple symmetric lipomatosis

Cited by 8 publications

References 23 publications

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

White Adipose Tissue Expansion in Multiple Symmetric Lipomatosis Is Associated with Upregulation of CK2, AKT and ERK1/2

<p>Cbl Proto-Oncogene B (CBLB) c.197A>T Mutation Induces Mild Metabolic Dysfunction in Partial Type I Multiple Symmetric Lipomatosis (MSL)</p>

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