LMNA R482Q mutation in partial lipodystrophy associated with reduced plasma leptin concentration

J Clin Endocrinol Metab. 2000 Sep;85(9):3089-93. doi: 10.1210/jcem.85.9.6768.


Mutations in LMNA, which encodes lamins A and C, have been found in patients with autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). We analyzed the relationship between plasma leptin and the rare LMNA R482Q mutation in 23 adult FPLD subjects compared with 25 adult family controls with normal LMNA in an extended Canadian FPLD kindred. We found that the LMNA Q482/R482 genotype was a significant determinant of plasma leptin, the ratio of plasma leptin to body mass index (BMI), plasma insulin, and plasma C peptide (P= 0.015, P = 0.0007, P = 0.0004, and P < 0.0001, respectively), but not BMI (P = 0.67). Family members who were heterozygous for LMNA Q482/R482 had significantly lower plasma leptin and leptin:BMI ratio than unaffected R482/R482 homozygotes. Fasting plasma concentrations of insulin and C peptide were both significantly higher in LMNA Q482/R482 heterozygotes than in R482/R482 homozygotes. Multivariate regression analysis revealed that the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%, respectively, of the attributable variation in log leptin, leptin:BMI ratio, log insulin, and log C peptide (P = 0.013, P = 0.0007, P = 0.0002 and P < 0.0001, respectively). The results indicate that a rare FPLD mutation in LMNA determines the plasma leptin concentration. It remains to be established whether the reduction in leptin results from the reduced adipose tissue mass in FPLD or from another subcellular effect of mutant LMNA. It also remains to be established whether the insulin resistance in FPLD is a consequence of the reduced plasma leptin or of another functional change resulting from mutant LMNA.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Body Mass Index
  • C-Peptide / blood
  • Female
  • Genotype
  • Humans
  • Insulin / blood
  • Lamins
  • Leptin / blood*
  • Leptin / deficiency
  • Lipodystrophy / blood
  • Lipodystrophy / genetics*
  • Male
  • Multivariate Analysis
  • Mutation / genetics*
  • Nuclear Proteins / genetics*


  • C-Peptide
  • Insulin
  • Lamins
  • Leptin
  • Nuclear Proteins