Lipodystrophic laminopathies: Diagnostic clues

Guillín-Amarelle, Cristina; Fernández-Pombo, Antía; Sánchez-Iglesias, Sofía; Araújo‐Vilar, David

doi:10.1080/19491034.2018.1454167

Cited by 27 publications

(25 citation statements)

References 92 publications

(113 reference statements)

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“…From a clinical point of view, FPLD2 and MADA feature type A lipodystrophy, i.e., a loss of fat from the limbs and trunk and accumulation in the neck, while MADB presents with a generalized loss of adipose tissue (type B lipodystrophy) [ 122 ]. Metabolic alterations such as insulin resistance, diabetes, dyslipidemia, and nonalcoholic fatty liver diseases are found in laminopathic lipodystrophies with some variability among individuals [ 51 ].…”

Section: Fpld2mentioning

confidence: 99%

“…Metabolic alterations such as insulin resistance, diabetes, dyslipidemia, and nonalcoholic fatty liver diseases are found in laminopathic lipodystrophies with some variability among individuals [ 51 ]. The onset of lipodystrophy is at puberty, while up to that age most mutation carriers appear unaffected [ 122 ]. Of note, fat loss is much more evident in females and some male patients remain asymptomatic for several years [ 122 ].…”

Section: Fpld2mentioning

confidence: 99%

“…The onset of lipodystrophy is at puberty, while up to that age most mutation carriers appear unaffected [ 122 ]. Of note, fat loss is much more evident in females and some male patients remain asymptomatic for several years [ 122 ]. A main clinical phenotype in MADA and MADB is accelerated ageing with onset in the second decade [ 1 ].…”

Section: Fpld2mentioning

confidence: 99%

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The Cutting Edge: The Role of mTOR Signaling in Laminopathies

Chiarini

Evangelisti

Cenni

et al. 2019

IJMS

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The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.

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Section: Fpld2mentioning

confidence: 99%

Section: Fpld2mentioning

confidence: 99%

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The Cutting Edge: The Role of mTOR Signaling in Laminopathies

Chiarini

Evangelisti

Cenni

et al. 2019

IJMS

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“…Regarding FPLD2, mutations located on the residue 482 are responsible for 80% of the cases and are associated with the classical clinical form [9]. Interestingly, women are more often diagnosed than men due to the android appearance characterized by protruding and well-defined musculature [10,11].…”

Section: Introductionmentioning

confidence: 99%

Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls

Desgrouas

Varlet

Dutour

et al. 2020

Cells

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This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

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“…FPLD2 or Dunnigan syndrome is a tissue-specific laminopathy affecting the adipose tissue and characterized by a loss of subcutaneous adipose tissue in the trunk, buttocks and limbs; fat accumulation in the neck, face, axillary and pelvic regions; apparent muscular hypertrophy; and metabolic dysfunctions (MDs), such as insulin resistance, diabetes mellitus, dyslipidemia and liver steatosis. MDs in FPLD2 are associated with a high incidence of cardiovascular diseases, such as atherosclerosis and coronary disease [ 25 ]. FPLD2 results from at least 20 LMNA missense mutations; however, the recurrent p.R482W/Q substitutions are responsible for 80% of the cases.…”

Section: Introductionmentioning

confidence: 99%

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Varlet

Helfer

Badens

2020

Cells

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Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.

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Lipodystrophic laminopathies: Diagnostic clues

Cited by 27 publications

References 92 publications

The Cutting Edge: The Role of mTOR Signaling in Laminopathies

The Cutting Edge: The Role of mTOR Signaling in Laminopathies

Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

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