Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate function of lamin A/C in adipose tissues, we created mice with an adipocyte-specific loss of Lmna (LmnaADKO). Although LmnaADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. LmnaADKO mice exhibit a surprisingly mild metabolic dysfunction on a chow diet, but on a high fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas LmnaADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared to controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully-differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. LmnaADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.

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Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2

10.2337/figshare.14691045.v2 ◽

2021 ◽

Author(s):

Callie A.S. Corsa ◽

Carolyn M. Walsh ◽

Devika P. Bagchi ◽

Maria C. Foss Freitas ◽

Ziru Li ◽

...

Keyword(s):

Lamin A ◽

Postnatal Life ◽

Chow Diet ◽

Metabolic Dysfunction ◽

Mineral Density ◽

Adipose Tissues ◽

Partial Lipodystrophy ◽

Brown Adipose ◽

Familial Partial Lipodystrophy

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate function of lamin A/C in adipose tissues, we created mice with an adipocyte-specific loss of Lmna (LmnaADKO). Although LmnaADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. LmnaADKO mice exhibit a surprisingly mild metabolic dysfunction on a chow diet, but on a high fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas LmnaADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared to controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully-differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. LmnaADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.

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Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Cells ◽

10.3390/cells9091947 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1947

Author(s):

Alice-Anaïs Varlet ◽

Emmanuèle Helfer ◽

Catherine Badens

Keyword(s):

Mechanical Properties ◽

Signaling Pathways ◽

Metabolic Disorders ◽

Lamin A ◽

Partial Lipodystrophy ◽

Familial Partial Lipodystrophy ◽

Atherosclerotic Cardiovascular Diseases ◽

Almost All ◽

Type V

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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Case Report: An Atypical Form of Familial Partial Lipodystrophy Type 2 Due to Mutation in the Rod Domain of Lamin A/C

Frontiers in Endocrinology ◽

10.3389/fendo.2021.675096 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carolina Cecchetti ◽

M. Rosaria D’Apice ◽

Elena Morini ◽

Giuseppe Novelli ◽

Carmine Pizzi ◽

...

Keyword(s):

Genetic Diagnosis ◽

Coiled Coil ◽

Missense Variant ◽

Lamin A ◽

Metabolic Complications ◽

Partial Lipodystrophy ◽

Atypical Form ◽

Amino Terminal ◽

Familial Partial Lipodystrophy

PurposeFamilial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes.Methods and ResultsHere we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient’s cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically.ConclusionsThis report supports the idea that there are “atypical forms” of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

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