Phenotypic Heterogeneity in Patients with Familial Partial Lipodystrophy (Dunnigan Variety) Related to the Site of Missense Mutations in Lamin A/C Gene

2001 ◽  
Vol 86 (1) ◽  
pp. 59-65 ◽  
Author(s):  
A. Garg
Keyword(s):  
Phenotypic Heterogeneity ◽  
Lamin A ◽  
Missense Mutations ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy

scholarly journals Heterogeneity of Nuclear Lamin A Mutations in Dunnigan-Type Familial Partial Lipodystrophy*

2000 ◽  
Vol 85 (9) ◽  
pp. 3431-3435
Author(s):  
Robert A. Hegele ◽  
Henian Cao ◽  
Carol M. Anderson ◽  
Irene M. Hramiak
Keyword(s):  
Environmental Factors ◽  
Novel Mutation ◽  
Compound Heterozygote ◽  
Lamin A ◽  
Missense Mutations ◽  
Compound Heterozygosity ◽  
Partial Lipodystrophy ◽  
Nuclear Lamin ◽  
Familial Partial Lipodystrophy ◽  
Affected Subject

Abstract We previously identified a novel mutation, namely LMNA R482Q, that was found to underlie Dunnigan-type partial lipodystrophy (FPLD) and diabetes in an extended Canadian kindred. We have since sequenced LMNA in five additional Canadian FPLD probands and herein report three new rare missense mutations in LMNA: V440M, R482W, and R584H. One severely affected subject was a compound heterozygote for both V440M and R482Q. The findings indicated that 1) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not lamin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence that is specific for lamin A; 3) the V440M mutation may not cause lipodystrophy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipodystrophy; and 5) variation in the severity of the phenotype might be related to environmental factors.

scholarly journals Expression of a Mutant Lamin A That Causes Emery-Dreifuss Muscular Dystrophy Inhibits In Vitro Differentiation of C2C12 Myoblasts

2004 ◽  
Vol 24 (4) ◽  
pp. 1481-1492 ◽  
Author(s):  
Catherine Favreau ◽  
Dominique Higuet ◽  
Jean-Claude Courvalin ◽  
Brigitte Buendia
Keyword(s):  
Muscular Dystrophy ◽  
Lamin A ◽  
Missense Mutations ◽  
In Vitro Differentiation ◽  
Partial Lipodystrophy ◽  
Frequent Mutations ◽  
Familial Partial Lipodystrophy ◽  
Low Levels ◽  
A Site

ABSTRACT Autosomal dominantly inherited missense mutations in lamins A and C cause several tissue-specific diseases, including Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD). Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD. In contrast with clones expressing wild-type lamin A, these clones differentiate poorly or not at all, do not exit the cell cycle properly, and are extensively committed to apoptosis. These disorders are correlated with low levels of expression of transcription factor myogenin and with the persistence of a large pool of hyperphosphorylated retinoblastoma protein. Since clones mutated at arginine 482 (a site responsible for FPLD) differentiate normally, we conclude that C2C12 clones expressing R453W-mutated lamin A represent a good cellular model to study the pathophysiology of EDMD. Our hypothesis is that lamin A mutated at arginine 453 fails to build a functional scaffold and/or to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.

scholarly journals Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Cells ◽  
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.

Spectrum of nuclear lamin A/C mutations and metabolic phenotypes in familial partial lipodystrophy

2000 ◽  
Vol 151 (1) ◽  
pp. 80
Author(s):  
RobertA. Hegele ◽  
CarolM. Anderson ◽  
Jian Wang ◽  
Henian Cao
Keyword(s):  
Lamin A ◽  
Partial Lipodystrophy ◽  
Metabolic Phenotypes ◽  
Nuclear Lamin ◽  
Familial Partial Lipodystrophy
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