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

Damien Galant (1) , Benedicte Gaborit (2, 3) , Camille Desgrouas (4, 1) , Inès Abdesselam (5, 3) , Monique Bernard (5) , Nicolas Lévy (1, 6) , Françoise Merono (1) , Catherine Coirault (7) , Patrice Roll (1, 8) , Arnaud Lagarde (1) , Nathalie Bonello-Palot (9, 10, 1) , Patrice Bourgeois (1, 11) , Anne Dutour (3, 12) , Catherine Badens (1, 9)

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 APHM - Assistance Publique - Hôpitaux de Marseille
3 NORT - Nutrition, obésité et risque thrombotique
4 AMU PHARM - Aix-Marseille Université - Faculté de pharmacie
5 CRMBM - Centre de résonance magnétique biologique et médicale
6 Département de génétique médicale [Hôpital de la Timone - APHM]
7 Centre de recherche en myologie
8 Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM]
9 Centre de référence maladie rare Thalassémie
10 Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM]
11 Neuro-Oncologie [Hôpital de la Timone - APHM]
12 Service d'Endocrinologie, Maladies Métaboliques et de la Nutrition

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

Domains: Life Sciences [q-bio]; Bioengineering

Damien Galant, Benedicte Gaborit, Camille Desgrouas, Inès Abdesselam, Monique Bernard, et al.. A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy. Cells, 2016, 5 (2), pp.21. ⟨10.3390/cells5020021⟩. ⟨hal-01425516⟩