ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.

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.

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