Association Between Nuclear Lamin A/C R482Q Mutation and Partial Lipodystrophy with Hyperinsulinemia, Dyslipidemia, Hypertension, and Diabetes

Abstract

Nuclear lamins A and C are encoded by LMNA and are present in terminally differentiated cells. Lamins participate in DNA replication, chromatin organization, arrangement of nuclear pores, nuclear growth, and anchorage of nuclear membranes. In several Canadian probands with partial lipodystrophy, since found to have a common ancestor, we identified a rare novel LMNA mutation, R482Q, that completely cosegregated with the partial lipodystrophy phenotype. We evaluated the relationship between quantitative metabolic phenotypes in both diabetic and nondiabetic carriers of LMNA R482Q and family controls, who were LMNA R482/R482 homozygotes. We found that when compared with LMNA R482/R482 homozygotes: (1) diabetic LMNA Q482/R482 heterozygotes had significantly higher glucose, glycosylated hemoglobin, triglycerides, insulin and C-peptide, and significantly lower HDL cholesterol; and (2) nondiabetic LMNA Q482/R482 heterozygotes had significantly higher triglycerides, insulin and C-peptide, and significantly lower HDL cholesterol. We also found that diabetic LMNA Q482/R482 heterozygotes were older and more likely to take antihypertensive medications. Thus, LMNA R482Q was associated with lipodystrophy, hyperinsulinemia, dyslipidemia, diabetes, and hypertension. The results indicate that perturbations in plasma lipids precede the plasma glucose abnormalities in LMNA Q482-associated hyperinsulinemia. Thus, rare mutations in a nuclear structural protein can be associated with markedly abnormal qualitative and quantitative metabolic phenotypes

Variation in the Lamin A/C Gene

“…Because mutations in LMNA have been associated previously with diabetes 20 and dyslipidemia, 44 we examined the relationship of LMNA polymorphisms identified in the Amish with the metabolic syndrome and its component traits. For the quantitative traits associated with metabolic syndrome (ie, glucose, obesity, and lipid levels), we estimated mean trait levels according to LMNA genotypes, whereas for the qualitative traits (metabolic syndrome, T2DM, and abnormal glucose tolerance), we compared disease prevalence across genotypes.…”

“…Excellent positional candidate genes include APOA (apolipoprotein A2), 6 PBX1 (pre-B-cell leukemia transcription factor 1), 7 slc19a2 (solute carrier family 19 [thiamine transporter] member 2), 8 INSRR (insulin receptor-related receptor gene), 9 KCNJ9 and KCNJ10 (potassium inwardly-rectifying channel, subfamily J, members 9 and 10), 10 18,19 and LMNA (lamin A/C). 20 This region is approximately 160 to 180 cM from p-telomere and corresponds to a region of chromosome 1 that has been linked to T2DM in several other populations, including Pima Indians, 21 Utah Mormons, 22 British whites, 23 French whites, 24 and Chinese. 25 Familial partial lipodystrophy is a condition associated with severe insulin resistance, diabetes, dyslipidemia, and atherosclerosis, 26 making LMNA an excellent positional candidate gene for metabolic syndrome, T2DM, and related traits.…”

Fat poetry: a kingdom for PPARγ

“…In 50% of the FPLD families, there is a link between FPLD and the LMNA (lamin A) gene also associated with premature forms of aging, which codes for the nuclear envelope protein lamin A/C [130]. Different mutations in this gene have been identified as culprits for lipodystrophy, but the mechanism by which it occurs is not known [131][132][133]. Mutations in the LMNA gene are linked to a decrease in the plasma concentrations of adiponectin and leptin, and an increase in circulating TNF-α concentrations, which may cause the insulin resistance observed in FPLD patients [134].…”

Laminopathies and Atherosclerosis

“…14 Careful phenotypic or "phenomic" studies performed in extended FPLD2 kindreds have shown metabolic changes that were similar to those seen in the common MetS. 15,16 In young adulthood, the characteristic biochemical profile seen in FPLD2 carriers of mutant LMNA included elevated plasma concentrations of free fatty acids, insulin and C-peptide, TG, and C-reactive protein (CRP), with depressed plasma concentrations of HDL cholesterol, leptin, and adiponectin. 15,16 Depressed adiponectin in particular could be a potent atherosclerosis risk factor in lipodystrophy syndromes.…”

“…15,16 In young adulthood, the characteristic biochemical profile seen in FPLD2 carriers of mutant LMNA included elevated plasma concentrations of free fatty acids, insulin and C-peptide, TG, and C-reactive protein (CRP), with depressed plasma concentrations of HDL cholesterol, leptin, and adiponectin. 15,16 Depressed adiponectin in particular could be a potent atherosclerosis risk factor in lipodystrophy syndromes. Hypertension usually presents next, followed by T2DM that causes profound changes in the metabolic intermediate traits.…”