{"title":"Rare ZMPSTE24 variants increase risk of hypertriglyceridemia and metabolic syndrome.","authors":"Lauriane Le Collen, Camille Desgrouas, Céline Lukas Croisier, Brunot Creugnet, Aurélie Dechaume, Bénédicte Toussaint, Emmanuel Vaillant, Souhila Amanzougarene, Emmanuel Buse Falay, Mehdi Derhourhi, Alexandre Lourdelle, Brigitte Delemer, Nathalie Bonello-Palot, Martine Vaxillaire, Catherine Badens, Philippe Froguel, Amélie Bonnefond","doi":"10.1093/ejendo/lvaf031","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>The global increase in the prevalence of metabolic syndrome represents a significant public health concern. Rare biallelic pathogenic variants in ZMPSTE24 have been identified as the cause of mandibuloacral dysplasia type B, ie, a lipodystrophy syndrome associated with metabolic complications. The role of monoallelic pathogenic variants in ZMPSTE24 concerning metabolic syndrome remains uncertain.</p><p><strong>Design: </strong>Case report and systematic review of literature.</p><p><strong>Methods: </strong>We investigated a Wallisian family with FPLD and metabolic syndrome via whole-exome sequencing. We performed functional analyses of an identified rare ZMPSTE24 variant. To broadly assess the effect of heterozygous pathogenic ZMPSTE24 variants on FPLD-associated phenotypes, and metabolic syndrome, we used the Human Gene Mutation Database (HGMD) and 200 K exome data from UK Biobank.</p><p><strong>Results: </strong>We investigated a Wallisian family where a 40-year-old female with metabolic syndrome was found to carry a rare heterozygous missense variant in ZMPSTE24. Functional assays showed a decreased prelamin to lamin A maturation and accelerated senescence. In silico analysis demonstrated that this variant might disrupt the lamin A binding site. We then analyzed the impact of monoallelic pathogenic ZMPSTE24 variants on metabolic traits using data from the HGMD and the UK Biobank. In HGMD, ZMPSTE24 variants carriers presented with dyslipidemia and hepatic steatosis. In the UK Biobank, monoallelic pathogenic variants were associated with an increased risk of hypertriglyceridemia, with a trend toward metabolic syndrome.</p><p><strong>Conclusions: </strong>This study underscores the association of ZMPSTE24 rare variants with metabolic disorders and emphasizes the need for further research to clarify their clinical implications.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"240-247"},"PeriodicalIF":5.3000,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ejendo/lvaf031","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Objective: The global increase in the prevalence of metabolic syndrome represents a significant public health concern. Rare biallelic pathogenic variants in ZMPSTE24 have been identified as the cause of mandibuloacral dysplasia type B, ie, a lipodystrophy syndrome associated with metabolic complications. The role of monoallelic pathogenic variants in ZMPSTE24 concerning metabolic syndrome remains uncertain.
Design: Case report and systematic review of literature.
Methods: We investigated a Wallisian family with FPLD and metabolic syndrome via whole-exome sequencing. We performed functional analyses of an identified rare ZMPSTE24 variant. To broadly assess the effect of heterozygous pathogenic ZMPSTE24 variants on FPLD-associated phenotypes, and metabolic syndrome, we used the Human Gene Mutation Database (HGMD) and 200 K exome data from UK Biobank.
Results: We investigated a Wallisian family where a 40-year-old female with metabolic syndrome was found to carry a rare heterozygous missense variant in ZMPSTE24. Functional assays showed a decreased prelamin to lamin A maturation and accelerated senescence. In silico analysis demonstrated that this variant might disrupt the lamin A binding site. We then analyzed the impact of monoallelic pathogenic ZMPSTE24 variants on metabolic traits using data from the HGMD and the UK Biobank. In HGMD, ZMPSTE24 variants carriers presented with dyslipidemia and hepatic steatosis. In the UK Biobank, monoallelic pathogenic variants were associated with an increased risk of hypertriglyceridemia, with a trend toward metabolic syndrome.
Conclusions: This study underscores the association of ZMPSTE24 rare variants with metabolic disorders and emphasizes the need for further research to clarify their clinical implications.
期刊介绍:
European Journal of Endocrinology is the official journal of the European Society of Endocrinology. Its predecessor journal is Acta Endocrinologica.
The journal publishes high-quality original clinical and translational research papers and reviews in paediatric and adult endocrinology, as well as clinical practice guidelines, position statements and debates. Case reports will only be considered if they represent exceptional insights or advances in clinical endocrinology.
Topics covered include, but are not limited to, Adrenal and Steroid, Bone and Mineral Metabolism, Hormones and Cancer, Pituitary and Hypothalamus, Thyroid and Reproduction. In the field of Diabetes, Obesity and Metabolism we welcome manuscripts addressing endocrine mechanisms of disease and its complications, management of obesity/diabetes in the context of other endocrine conditions, or aspects of complex disease management. Reports may encompass natural history studies, mechanistic studies, or clinical trials.
Equal consideration is given to all manuscripts in English from any country.