Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls
This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in <i>LMNA</i>, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fa...
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| Format: | Article |
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MDPI AG
2020-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/2/310 |
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| author | Camille Desgrouas Alice-Anaïs Varlet Anne Dutour Damien Galant Françoise Merono Nathalie Bonello-Palot Patrice Bourgeois Adèle Lasbleiz Cathy Petitjean Patricia Ancel Nicolas Levy Catherine Badens Bénédicte Gaborit |
| author_facet | Camille Desgrouas Alice-Anaïs Varlet Anne Dutour Damien Galant Françoise Merono Nathalie Bonello-Palot Patrice Bourgeois Adèle Lasbleiz Cathy Petitjean Patricia Ancel Nicolas Levy Catherine Badens Bénédicte Gaborit |
| author_sort | Camille Desgrouas |
| collection | DOAJ |
| description | This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in <i>LMNA</i>, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in <i>LMNA</i> are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping. |
| first_indexed | 2024-03-12T09:21:32Z |
| format | Article |
| id | doaj.art-b80c42a72b334a378e9c101f1dcf8c37 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:21:32Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-b80c42a72b334a378e9c101f1dcf8c372023-09-02T14:29:51ZengMDPI AGCells2073-44092020-01-019231010.3390/cells9020310cells9020310Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical PitfallsCamille Desgrouas0Alice-Anaïs Varlet1Anne Dutour2Damien Galant3Françoise Merono4Nathalie Bonello-Palot5Patrice Bourgeois6Adèle Lasbleiz7Cathy Petitjean8Patricia Ancel9Nicolas Levy10Catherine Badens11Bénédicte Gaborit12Aix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, INRAE, C2VN, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, INRAE, C2VN, 13005 Marseille, FranceAPHM, Endocrinology, Metabolic diseases and nutrition department, 13005 Marseille, FranceAix Marseille Université, INSERM, INRAE, C2VN, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, MMG, 13005 Marseille, FranceAix Marseille Université, INSERM, INRAE, C2VN, 13005 Marseille, FranceThis study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in <i>LMNA</i>, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in <i>LMNA</i> are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.https://www.mdpi.com/2073-4409/9/2/310dyslipidemiametabolic syndromeinsulin resistancelamin a/cnuclear anomalies and premature senescence |
| spellingShingle | Camille Desgrouas Alice-Anaïs Varlet Anne Dutour Damien Galant Françoise Merono Nathalie Bonello-Palot Patrice Bourgeois Adèle Lasbleiz Cathy Petitjean Patricia Ancel Nicolas Levy Catherine Badens Bénédicte Gaborit Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls Cells dyslipidemia metabolic syndrome insulin resistance lamin a/c nuclear anomalies and premature senescence |
| title | Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls |
| title_full | Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls |
| title_fullStr | Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls |
| title_full_unstemmed | Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls |
| title_short | Unraveling <i>LMNA</i> Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls |
| title_sort | unraveling i lmna i mutations in metabolic syndrome cellular phenotype and clinical pitfalls |
| topic | dyslipidemia metabolic syndrome insulin resistance lamin a/c nuclear anomalies and premature senescence |
| url | https://www.mdpi.com/2073-4409/9/2/310 |
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