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.

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

“…Hepatic steatosis is a common phenotype for aged mice (Jin et al., 2010; Ogrodnik et al., 2017), Zmpste24 mutants (Marino et al., 2008; Pendas et al., 2002), and liver‐specific Lmna knockouts (Kwan et al., 2017). In addition, mutations in LMNA and ZMPSTE24 in patients lead to metabolic dysfunction, including type 2 diabetes and hepatic steatosis (Galant et al., 2016; Shackleton et al., 2000). Moreover, a recent report has implicated disorganization of heterochromatin at the lamina as a driver of human aging (Zhang et al., 2015).…”

ZMPSTE24Missense Mutations that Cause Progeroid Diseases Decrease Prelamin A Cleavage Activity and/or Protein Stability

“…In general, the severity of these three progeroid diseases reflects the amount of permanently farnesylated and carboxyl methylated prelamin A that accumulates per cell. Recently individuals with metabolic syndrome and nonalchoholic fatty liver disease (NAFLD), both lipodystrophy-associated disorders, were also found to have a ZMPSTE24 missense mutation (Table 1) (Brady et al, 2017;Dutour et al, 2011;Galant et al, 2016). In addition, diminished ZMPSTE24 processing of prelamin A may be important in normal aging, based on a study showing that prelamin A accumulation occurs in blood vessels from aging, and not young, individuals (Ragnauth et al, 2010).…”

Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide

“…Several new mutations in ZMPSTE24 have recently been reported in MADB or RD (Navarro et al 2014; Wang et al 2016). A heterozygous ZMPSTE24 mutation is also shown to be associated with severe metabolic syndrome, abnormal fat accumulation, and dilated cardiomyopathy (Galant et al 2016). …”