A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome
We report a new laminopathy that includes generalized lipoatrophy, insulin-resistant diabetes, micrognathia and biopsy-proven, focal segmental glomerulosclerosis in a female, caused by a de novo heterozygous mutation R133L in the lamin A/C gene (LMNA). We analysed the nuclear morphology and laminar...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Adipocyte |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21623945.2019.1640007 |
| _version_ | 1818127047025754112 |
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| author | Zhe Wang Yueting Dong Jing Yang Yingzi He Xihua Lin Fang Wu Hong Li Fenping Zheng |
| author_facet | Zhe Wang Yueting Dong Jing Yang Yingzi He Xihua Lin Fang Wu Hong Li Fenping Zheng |
| author_sort | Zhe Wang |
| collection | DOAJ |
| description | We report a new laminopathy that includes generalized lipoatrophy, insulin-resistant diabetes, micrognathia and biopsy-proven, focal segmental glomerulosclerosis in a female, caused by a de novo heterozygous mutation R133L in the lamin A/C gene (LMNA). We analysed the nuclear morphology and laminar distribution in 3T3-L1 pre-adipocytes overexpressing human wild-type lamin A/C (LMNA WT) or lamin A/C with the R133L mutation (LMNA R133L). We found the nuclear size was varied, nuclear membrane invagination or blebbing, and an irregular A-type lamin meshwork in cells overexpressing LMNA R133L.3T3-L1 pre-adipocyte differentiation into adipocytes was impaired in cells expressing LMNA R133L; contemporaneously, the expression levels of genes associated with adipose tissue self-renewal, including adipogenesis, angiogenesis, and extracellular matrix maintenance, were downregulated. Furthermore, the insulin-signalling pathway was inhibited in LMNA R133L adipocytes. Microarray gene expression profiling showed that the most prominent differences between 3T3-L1 cells expressing wild-type LMNA and LMNA R133L were in genes implicated in metabolic pathways, the cellular response to DNA damage and repair. We thus expand the clinical spectrum of laminopathy and conclude that the LMNA R133L mutation associated with lipodystrophic features and multisystem disorders likely impairs adipocyte renewal and disrupts the expression of genes implicated in the induction and repair of DNA damage. |
| first_indexed | 2024-12-11T07:11:08Z |
| format | Article |
| id | doaj.art-2a16cc0a0aae40a4b0a59000986ee479 |
| institution | Directory Open Access Journal |
| issn | 2162-3945 2162-397X |
| language | English |
| last_indexed | 2024-12-11T07:11:08Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Adipocyte |
| spelling | doaj.art-2a16cc0a0aae40a4b0a59000986ee4792022-12-22T01:16:20ZengTaylor & Francis GroupAdipocyte2162-39452162-397X2019-01-018128029110.1080/21623945.2019.16400071640007A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptomeZhe Wang0Yueting Dong1Jing Yang2Yingzi He3Xihua Lin4Fang Wu5Hong Li6Fenping Zheng7The Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityThe Affiliated Sir Run Run Shaw Hospital, College of Medicine, Zhejiang UniversityWe report a new laminopathy that includes generalized lipoatrophy, insulin-resistant diabetes, micrognathia and biopsy-proven, focal segmental glomerulosclerosis in a female, caused by a de novo heterozygous mutation R133L in the lamin A/C gene (LMNA). We analysed the nuclear morphology and laminar distribution in 3T3-L1 pre-adipocytes overexpressing human wild-type lamin A/C (LMNA WT) or lamin A/C with the R133L mutation (LMNA R133L). We found the nuclear size was varied, nuclear membrane invagination or blebbing, and an irregular A-type lamin meshwork in cells overexpressing LMNA R133L.3T3-L1 pre-adipocyte differentiation into adipocytes was impaired in cells expressing LMNA R133L; contemporaneously, the expression levels of genes associated with adipose tissue self-renewal, including adipogenesis, angiogenesis, and extracellular matrix maintenance, were downregulated. Furthermore, the insulin-signalling pathway was inhibited in LMNA R133L adipocytes. Microarray gene expression profiling showed that the most prominent differences between 3T3-L1 cells expressing wild-type LMNA and LMNA R133L were in genes implicated in metabolic pathways, the cellular response to DNA damage and repair. We thus expand the clinical spectrum of laminopathy and conclude that the LMNA R133L mutation associated with lipodystrophic features and multisystem disorders likely impairs adipocyte renewal and disrupts the expression of genes implicated in the induction and repair of DNA damage.http://dx.doi.org/10.1080/21623945.2019.1640007laminopathylamin a/cadipocyte differentiationinsulin resistancedna damage |
| spellingShingle | Zhe Wang Yueting Dong Jing Yang Yingzi He Xihua Lin Fang Wu Hong Li Fenping Zheng A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome Adipocyte laminopathy lamin a/c adipocyte differentiation insulin resistance dna damage |
| title | A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome |
| title_full | A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome |
| title_fullStr | A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome |
| title_full_unstemmed | A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome |
| title_short | A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome |
| title_sort | new laminopathy caused by an arg133 leu mutation in lamin a c and the effects thereof on adipocyte differentiation and the transcriptome |
| topic | laminopathy lamin a/c adipocyte differentiation insulin resistance dna damage |
| url | http://dx.doi.org/10.1080/21623945.2019.1640007 |
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