High prevalence of laminopathies among patients with metabolic syndrome

Abstract

Constitutional laminopathies, such as the Dunnigan familial partial lipodystrophy, are severe diseases caused by mutations in A-type lamins and share several features with metabolic syndrome (MS). In this study, we hypothesized that MS may be, in some cases, a mild form of laminopathies and use the abnormal cell nucleus phenotype observed in these diseases as a primary screening test in patients suffering from common MS. Nuclear shape and lamin A nucleoplasmic distribution abnormalities were systematically searched in lymphoblastoid cells of 87 consecutive patients with MS. In parallel, five genes encoding either the A-type lamins or the enzymes of the lamin A maturation pathway were systematically sequenced (LMNA, ZMPSTE24, ICMT, FNTA and FNTB). We identified 10 MS patients presenting abnormal nuclear shape and disturbed lamin A/C nuclear distribution. These patients were not clinically different from those without nuclear abnormalities except that they were younger, and had higher triglyceridemia and SGPT levels. Three of them carry a heterozygous mutation in LMNA or in ZMPSTE24, a gene encoding one of the lamin A processing enzymes. All three mutations are novel missense mutations predicted to be damaging. Both lymphoblastoid cells and skin fibroblasts from the patient carrying the mutation in ZMPSTE24, showed accumulation of lamin A precursor, indicating an alteration of the lamin A processing, confirmed by functional study. Together, these results show for the first time, that a significant proportion of MS patients exhibits laminopathies and suggest that systematic investigation of lamin A and its partners should be performed at the diagnosis of this syndrome.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…Nonetheless, recently, a heterozygous (c.1312C4T, p.Leu438Phe) mutation was identified in a patient affected with a metabolic syndrome. 36 In this patient, slight prelamin A accumulation was detected by immunofluorescence analyses in fibroblasts, associated with nuclear abnormalities. In this case, processing of prelamin A was not complete as demonstrated by ELISA.…”

Lipodystrophies: adipose tissue disorders with severe metabolic implications

“…Similarly, Dutour et al showed that 10 out of 87 patients with common metabolic syndrome had morphological abnormalities in their cell nuclei suggestive of FPL type 2 [14]. Sequencing analysis revealed that 3 of these 10 patients carried previously unreported missense mutations in LMNA or ZMPSTE24, encoding a zinc metalloprotease which genetic variants are known to cause laminopathy [14].…”

“…A study of 5000 ambulatory controlled diabetic patients found that among those with body mass index <27 m 2 /kg and high insulin requirements (>100 U/day), there were five subjects with previously unrecognized FPL [55]. Similarly, Dutour et al showed that 10 out of 87 patients with common metabolic syndrome had morphological abnormalities in their cell nuclei suggestive of FPL type 2 [14]. Sequencing analysis revealed that 3 of these 10 patients carried previously unreported missense mutations in LMNA or ZMPSTE24, encoding a zinc metalloprotease which genetic variants are known to cause laminopathy [14].…”

Nuclear lamins and laminopathies

“…In contrast, amino acids substitutions in the immunoglobulin-like fold that occur in striated muscle diseases are predicted to lead to significant overall disruption of its tertiary structure [4,5]. Various other mutations in LMNA have been reported in subjects with abnormalities in adipose tissue, insulin sensitivity and fat metabolism but without the typical Dunnigan-type familial partial lipodystrophy phenotype [48][49][50].…”