Phenotypic Heterogeneity in Body Fat Distribution in Patients with Atypical Werner’s Syndrome Due to Heterozygous Arg133Leu Lamin A/C Mutation

Jacob, Katherine N.; Baptista, Fernando Oliveira; Santos, Heloísa G. dos; Oshima, Junko; Agarwal, Anil K.; Garg, Abhimanyu

doi:10.1210/jc.2005-0939

Cited by 31 publications

(41 citation statements)

References 27 publications

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“…They are often correlated with the severity of the complications within patients carrying the same LMNA mutations [53,54]. For instance, we reported two female patients, one AfricanAmerican and one Caucasian, who shared the same R133L mutation but had vastly different body fat distribution.…”

Section: Discussionmentioning

confidence: 90%

“…For instance, we reported two female patients, one AfricanAmerican and one Caucasian, who shared the same R133L mutation but had vastly different body fat distribution. The extent of the lipodystrophy appeared to be correlated with the severity of the metabolic complications and also the degree of abnormal nuclear morphology [53]. A study examining three homozygotes for the R527H mutation and the same clinical phenotype demonstrated that the extent of nuclear and heterochromatin irregularities were correlated with pre-lamin A accumulation and, interestingly, patient age [54].…”

Section: Discussionmentioning

confidence: 94%

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Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Huang

Risques

Martin

et al. 2008

Experimental Cell Research

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116

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LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. To our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectible WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 94%

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Huang

Risques

Martin

et al. 2008

Experimental Cell Research

Self Cite

116

View full text Add to dashboard Cite

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“…Some patients with MAD do not have mutations in either of these two loci suggesting the presence of additional loci. Both partial and generalized lipodystrophy has also been reported in patients with Hutchinson-Gilford progeria [30], and atypical progeroid syndrome due to heterozygous LMNA mutations [31]. In patients with neonatal progeroid syndrome, generalized diminution of subcutaneous fat has been reported, but it is often accompanied by concomitant reduction in skeletal muscle and lean body mass unlike other lipodystrophy syndromes [32].…”

Section: Lipodystrophy In Association With Other Syndromesmentioning

confidence: 99%

Lipodystrophies and Dyslipidemias

Garg

2015

Contemporary Endocrinology

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“…6D). The lamin A-R133L mutation is a dominant mutation found in patients with Werner's syndrome, which affects the structure of the lamina (Jacob et al, 2005). The lamin A-R220Q dominant mutation is localized at the variable linker L12, which connects the 1B and 2A α-helical segments found in various laminopathies (Dhe-Paganon et al, 2002;Broers et al, 2006).…”

Section: Telomeres Form Aggregates In Senescent Hmscsmentioning

confidence: 99%

The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells

Raz

Vermolen

Garini

et al. 2008

Journal of Cell Science

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Ex vivo, human mesenchymal stem cells (hMSCs) undergo spontaneous cellular senescence after a limited number of cell divisions. Intranuclear structures of the nuclear lamina were formed in senescent hMSCs, which are identified by the presence of Hayflick-senescence-associated factors. Notably, spatial changes in lamina shape were observed before the Hayflick senescence-associated factors, suggesting that the lamina morphology can be used as an early marker to identify senescent cells. Here, we applied quantitative image-processing tools to study the changes in nuclear architecture during cell senescence. We found that centromeres and telomeres colocalised with lamina intranuclear structures, which resulted in a preferred peripheral distribution in senescent cells. In addition, telomere aggregates were progressively formed during cell senescence. Once formed, telomere aggregates showed colocalization with γ-H2AX but not with TERT, suggesting that telomere aggregates are sites of DNA damage. We also show that telomere aggregation is associated with lamina intranuclear structures, and increased telomere binding to lamina proteins is found in cells expressing lamina mutants that lead to increases in lamina intranuclear structures. Moreover, three-dimensional image processing revealed spatial overlap between telomere aggregates and lamina intranuclear structures. Altogether, our data suggest a mechanical link between changes in lamina spatial organization and the formation of telomere aggregates during senescence of hMSCs, which can possibly contribute to changes in nuclear activity during cell senescence.

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Phenotypic Heterogeneity in Body Fat Distribution in Patients with Atypical Werner’s Syndrome Due to Heterozygous Arg133Leu Lamin A/C Mutation

Abstract: Atypical Werner's syndrome associated with Arg133Leu mutation in the LMNA gene presents with a phenotypically heterogeneous disorder. Furthermore, the severity of metabolic complications seems to correlate with the extent of lipodystrophy.

Cited by 31 publications

References 27 publications

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

Lipodystrophies and Dyslipidemias

The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells

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