A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

Abstract

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.

Keywords: ZMPSTE24; cardiomyopathy; laminopathy; metabolic syndrome; nuclear anomalies; premature senescence.

Figure 1

Patient’s description. (A) Photographs of the patient carrying the heterozygous ZMPSTE24 missense mutation L438F, showing an accumulation of facial and cervical fat, android obesity, acanthosis nigricans, and no lower limb lipoatrophy; (B) Abdominal CT scan and cardiac-MRI of the patient showing the presence of superficial and deep subcutaneous adipose tissue and accumulation of cardiac ectopic fat; (C) Quantification of patient epicardial fat volume, myocardial, and hepatic triglyceride content using 3T MRI and proton magnetic resonance spectroscopy (¹H-MRS). Comparison of patient’s ectopic fat depots with a group of type 2 diabetic subjects with metabolic syndrome matched for age and BMI.

Figure 2

Nuclear shape anomalies and senescence tests. (A) Representative pictures of nuclear anomalies. Upper panel: aberrant nuclear pattern, aberrant cytoplasmic localization and aberrant shape after lamin A staining. Fibroblasts were examined with Apotome.2 (Zeiss) stereomicroscope under oil immersion (100× magnification). Lower panel: representative pictures of nuclear anomalies with different staining (Lamin A/C, Lamin B and Emerin); (B) Quantitative estimation of dysmorphic nuclei in control and patient fibroblasts with and without siRNA. Asterisks correspond to p values of 0.0268; (C) Representative Western Blot and quantitative estimation of lamin A in patient fibroblasts with and without siRNA. Asterisk corresponds to a p value of 0.0286; (D) Population Doubling Level. ANOVA showed p < 0.0001 between control and patient PDL; (E) Senescence related beta-galactosidase activity before and 24h after siRNA treatment. The double asterisk corresponds to a p value of 0.0079; the asterisk corresponds to a p value of 0.0159. (F) BrdU incorporation. Asterisk corresponds to a p value of 0.0173. In all experiments, “control” was fibroblasts from healthy people.