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

Citation
Ra. Hegele et al., LMNA R482Q mutation in partial lipodystrophy associated with reduced plasma leptin concentration, J CLIN END, 85(9), 2000, pp. 3089-3093
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Endocrynology, Metabolism & Nutrition","Endocrinology, Nutrition & Metabolism
Journal title
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN journal
0021-972X → ACNP
Volume
85
Issue
9
Year of publication
2000
Pages
3089 - 3093
Database
ISI
SICI code
0021-972X(200009)85:9<3089:LRMIPL>2.0.ZU;2-X
Abstract
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.