Mutations in LMNA, which encodes lamins A and C, have been found in patient
s With autosomal dominant Dunnigan-type familial partial lipodystrophy (FPL
D). We analyzed the relationship between plasma leptin and the rare LMNA R4
8Q mutation in 23 adult FPLD subjects compared with 25 adult family control
s 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 plasm
a C peptide (P = 0.015, P = 0.0007, P = 0.0004, and P < 0.0001, respectivel
y), but not BMI (P = 0.67). Family members who were heterozygous for LMNA Q
482/R482 had significantly lower plasma leptin and leptin:BMI ratio than un
affected R482/R482 homozygotes. Fasting plasma concentrations of insulin an
d C peptide were both significantly higher in LMNA Q482/R482 heterozygotes
than in R482/R482 homozygotes. Multivariate regression analysis revealed th
at the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%, re
spectively, of the attributable Variation in log leptin, leptin:BMI ratio,l
og 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 w
hether 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.