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.