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.