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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

SUBMITTER: Hegele RA

PROVIDER: S-EPMC310873 | biostudies-literature | 2000 May

REPOSITORIES: biostudies-literature

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Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes.

Hegele R A RA Anderson C M CM Wang J J Jones D C DC Cao H H

Genome research 20000501 5

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 quanti ...[more]

PMID: 10810087

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Project description:Aims/hypothesisPartial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r-metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r-metHuLeptin.MethodsA 36-year-old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHuLeptin in lipodystrophy. The patient received escalating doses of r-metHuLeptin until a dose 0.12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy.ResultsEighteen months of r-MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8.3 mmol/l; 18 months = 4.9 mmol/l), lowering of HbA1c (baseline = 9.9%; 18 months = 7.2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21.15 mmol/l; 18 months = 5.96 mmol/l).Conclusionr-MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHuLeptin is independent of the aetiology in lipodystrophy.

Dataset Information

Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes.

Publications

Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes.

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