Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls

Cells

Cathy Petitjean¹  Adèle Lasbleiz²  Patricia Ancel²  Anne Dutour²  Bénédicte Gaborit²  Catherine Badens³  Damien Galant³  Nicolas Levy³  Nathalie Bonello-Palot³  Patrice Bourgeois³  Camille Desgrouas³  Françoise Merono³  Alice-Anaïs Varlet³ 

[1] APHM, Endocrinology, Metabolic diseases and nutrition department, 13005 Marseille, France;Aix Marseille Université, INSERM, INRAE, C2VN, 13005 Marseille, France;Aix Marseille Université, INSERM, MMG, 13005 Marseille, France;

关键词: dyslipidemia;    metabolic syndrome;    insulin resistance;    lamin a/c;    nuclear anomalies and premature senescence;   

DOI  :  10.3390/cells9020310

来源: DOAJ

【 摘 要 】

This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, 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 LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

【 授权许可】

Unknown