A Rare Mutation in LMNB2 Associated with Lipodystrophy Drives Premature Cell Senescence

Many proteins are causative for inherited partial lipodystrophies, including lamins, the essential constituents of the nuclear envelope scaffold called the lamina. By performing high throughput sequencing on a panel of genes involved in lipodystrophies, we identified a heterozygous mutation in LMNB2 gene (c.700C > T p.(Arg234Trp)) in a female patient presenting early onset type II diabetes, hypertriglyceridemia, and android fat distribution. This mutation is rare in the general population (frequency 0.013% in GnomAD) and was predicted pathogenic by a set of pathogenicity prediction software. Patient-derived fibroblasts showed nuclear shape abnormalities and premature senescence features, which are two typical cellular phenotypes associated with laminopathies. Moreover, we observed an atypical aggregation of lamin B2 in nucleoplasm, which co-distributes with emerin and lamin A/C, along with an abnormal distribution of lamin A/C at the nuclear envelope. Finally, reducing lamin B2 expression level by siRNA targeted toward LMNB2 transcripts resulted in decreased nuclear anomalies and senescence-associated beta-galactosidase, suggesting a role of the mutated protein in the occurrence of the observed cellular phenotype. Altogether, these results suggest that mutations in lamin B2 could produce premature senescence and partial lipodystrophy features as observed with certain mutants of lamin A/C.

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Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations

Muscle & Nerve ◽

10.1002/mus.20122 ◽

2004 ◽

Vol 30 (4) ◽

pp. 444-450 ◽

Cited By ~ 108

Author(s):

A. Muchir ◽

J. Medioni ◽

M. Laluc ◽

C. Massart ◽

T. Arimura ◽

...

Keyword(s):

Muscular Dystrophy ◽

Nuclear Envelope ◽

Gene Mutations ◽

Lamin A ◽

Partial Lipodystrophy

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Body fat distribution in women with familial partial lipodystrophy caused by mutation in the lamin A/C gene

Indian Journal of Endocrinology and Metabolism ◽

10.4103/2230-8210.91209 ◽

2012 ◽

Vol 16 (1) ◽

pp. 136 ◽

Cited By ~ 5

Author(s):

LucianaZ Monteiro ◽

RenanM Montenegro ◽

MiltonC Foss ◽

MariaC Foss-Freitas

Keyword(s):

Body Fat ◽

Fat Distribution ◽

Body Fat Distribution ◽

Lamin A ◽

Partial Lipodystrophy ◽

Familial Partial Lipodystrophy

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Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene

Journal of Cell Science ◽

10.1242/jcs.114.24.4459 ◽

2001 ◽

Vol 114 (24) ◽

pp. 4459-4468 ◽

Cited By ~ 5

Author(s):

Corinne Vigouroux ◽

Martine Auclair ◽

Emmanuelle Dubosclard ◽

Marcel Pouchelet ◽

Jacqueline Capeau ◽

...

Keyword(s):

Nuclear Envelope ◽

Primary Cultures ◽

Ectopic Expression ◽

Nuclear Pore ◽

Lamin A ◽

Nuclear Pore Complexes ◽

Intermediate Filament Proteins ◽

Partial Lipodystrophy ◽

Nuclear Alterations ◽

Pore Complexes

Dunnigan-type familial partial lipodystrophy (FPLD), characterized by an abnormal body fat redistribution with insulin resistance, is caused by missense heterozygous mutations in A-type lamins (lamins A and C). A- and B-type lamins are ubiquitous intermediate filament proteins that polymerize at the inner face of the nuclear envelope. We have analyzed primary cultures of skin fibroblasts from three patients harboring R482Q or R482W mutations. These cells were euploid and able to cycle and divide. A subpopulation of these cells had abnormal blebbing nuclei with A-type lamins forming a peripheral meshwork, which was frequently disorganized. Inner nuclear membrane protein emerin, an A-type lamin-binding protein, strictly colocalized with this abnormal meshwork. Cells from lipodystrophic patients often had other nuclear envelope defects, mainly consisting of nuclear envelope herniations that were deficient in B-type lamins, nuclear pore complexes, lamina-associated protein 2 beta, and chromatin. The mechanical properties of nuclear envelopes were altered, as judged from the extensive deformations observed in nuclei from heat-shocked cells, and from the low stringency of extraction of their components. These structural nuclear alterations were caused by the lamins A/C mutations, as the same changes were introduced in human control fibroblasts by ectopic expression of R482W mutated lamin A.

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A genome-wide linkage scan for familial partial lipodystrophy susceptibility genes in a German kindreds

Clinical & Investigative Medicine ◽

10.25011/cim.v30i4.2861 ◽

2007 ◽

Vol 30 (4) ◽

pp. 86

Author(s):

M. Lanktree ◽

J. Robinson ◽

J. Creider ◽

H. Cao ◽

D. Carter ◽

...

Keyword(s):

Subcutaneous Fat ◽

Visceral Obesity ◽

Fat Distribution ◽

Dominant Negative ◽

Molecular Forms ◽

Partial Lipodystrophy ◽

Genome Wide ◽

A Genome ◽

Familial Partial Lipodystrophy ◽

Promoter Mutations

Background: In Dunnigan-type familial partial lipodystrophy (FPLD) patients are born with normal fat distribution, but subcutaneous fat from extremities and gluteal regions are lost during puberty. The abnormal fat distribution leads to the development of metabolic syndrome (MetS), a cluster of phenotypes including hyperglycemia, dyslipidemia, hypertension, and visceral obesity. The study of FPLD as a monogenic model of MetS may uncover genetic risk factors of the common MetS which affects ~30% of adult North Americans. Two molecular forms of FPLD have been identified including FPLD2, resulting from heterozygous mutations in the LMNA gene, and FPLD3, resulting from both heterozygous dominant negative and haploinsufficiency mutations in the PPARG gene. However, many patients with clinically diagnosed FPLD have no mutation in either LMNA or PPARG, suggesting the involvement of additional genes in FPLD etiology. Methods: Here, we report the results of an Affymetrix 10K GeneChip microarray genome-wide linkage analysis study of a German kindred displaying the FPLD phenotype and no known lipodystrophy-causing mutations. Results: The investigation identified three chromosomal loci, namely 1q, 3p, and 9q, with non-parametric logarithm of odds (NPL) scores >2.7. While not meeting the criteria for genome-wide significance, it is interesting to note that the 1q and 3p peaks contain the LMNA and PPARG genes respectively. Conclusions: Three possible conclusions can be drawn from these results: 1) the peaks identified are spurious findings, 2) additional genes physically close to LMNA, PPARG, or within 9q, are involved in FPLD etiology, or 3) alternative disease causing mechanisms not identified by standard exon sequencing approaches, such as promoter mutations, alternative splicing, or epigenetics, are also responsible for FPLD.

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Faculty Opinions recommendation of Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030491.360418 ◽

2006 ◽

Author(s):

Yosef Gruenbaum

Keyword(s):

Adipocyte Differentiation ◽

Lamin A ◽

Partial Lipodystrophy ◽

Nuclear Lamin ◽

Familial Partial Lipodystrophy

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A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities

European Journal of Ophthalmology ◽

10.1177/11206721211008355 ◽

2021 ◽

pp. 112067212110083

Author(s):

Shu-Hua Ni ◽

Juan-Mei Zhang ◽

Jun Zhao

Keyword(s):

Missense Mutation ◽

High Throughput Sequencing ◽

Bioinformatics Analysis ◽

Genetic Defect ◽

Kinase Domain ◽

Chinese Family ◽

Heterozygous Mutation ◽

Scale Invariant ◽

The Family ◽

Northern Chinese

Purpose: To demonstrate the underlying genetic defect that contribute to inherited cataract in a northern Chinese pedigree. Methods: The study recruited a family pedigree with a diagnosis of bilateral coronary cataract with blue punctate opacities. Fourteen family members and 100 healthy volunteers were enrolled. DNA sample of the proband in this family were analyzed by high-throughput sequencing, which was then demonstrated by Sanger sequencing in the remained people in the family and 100 controls. The functional effect of mutant genes was investigated via bioinformatics analysis, including Polymorphism Phenotyping version2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN v1.1.3) Scale-Invariant Feature Transform (SIFT), and Mutation Taster. Results: In this three-generation family, a novel heterozygous mutation was found in the kinase domain of CRYBA1 gene (c.340C > T, p.R114C), which was only detected in patients in the family with inherited cataract and were not detected in the remained people in the family nor in normal people. The pathogenic effect of the mutation was verified via bioinformatics analysis. Conclusion: Our study presented the molecular experiments to confirm that a novel missense mutation of c.340 C > T located in exon 4 of CRYBA1 gene results in a bilateral coronary cataract with blue punctate opacities, which enriches the mutation spectrum of CRYBA1 gene in inherited cataract and deepens the understanding of the pathogenesis of inherited cataract.

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Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Physiological Genomics ◽

10.1152/physiolgenomics.00060.2005 ◽

2005 ◽

Vol 23 (2) ◽

pp. 150-158 ◽

Cited By ~ 80

Author(s):

Ilaria Filesi ◽

Francesca Gullotta ◽

Giovanna Lattanzi ◽

Maria Rosaria D'Apice ◽

Cristina Capanni ◽

...

Keyword(s):

Nuclear Envelope ◽

Protein A ◽

Nuclear Architecture ◽

Mendelian Inheritance ◽

Premature Aging ◽

Lamin A ◽

Lamin B ◽

Lamin B Receptor ◽

Epigenetic Events ◽

Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

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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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