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A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features.

ABSTRACT: Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis revealed abnormal nuclear morphology characteristic of laminopathies within primary fibroblast cultures, but not in a lymphoblastoid cell line, in keeping with previous observations. Our findings indicate that FPLD2 should be considered in the differential diagnosis of the Werner syndrome.

SUBMITTER: Saha B

PROVIDER: S-EPMC2957848 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features.

Saha B B Lessel D D Hisama F M FM Leistritz D F DF Friedrich K K Martin G M GM Kubisch C C Oshima J J

Molecular syndromology 20100914 3

Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis rev ...[more]

PMID: 21031082

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Project description:BackgroundFamilial partial lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD.MethodsWe evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial partial lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure.ResultsWe demonstrate that patients with FPLD show increased HbA1c (p < 0.01), fasting glucose (p < 0.002) and triglycerides (p < 0.005) while HDL/cholesterol (p < 0.001) was lower when compared to healthy individuals. We found that 64.2% FPLD patients had metabolic syndrome according to International Diabetes Federation definition. We also observe increased AUC of glucose (p < 0.001) and insulin during oGTT, featuring a frame of hyperglycemia and hyperinsulinemia, suggesting insulin resistance. Also we found hyperactivation of several genes responsible for ERS such as ATF-4 (p < 0.01), ATF-6 (p < 0.01), EIF2α3K (p < 0.005), CCT4 (p < 0.001), CHOP (p < 0.01), CALR (p < 0.001) and CANX (p < 0.005), that corroborate the idea that diabetes mellitus and metabolic syndrome are associated with direct damage to the endoplasmic reticulum homeostasis. Ultimately, we note that individuals with lipodystrophy have an increase in serum interleukins, keys of the inflammatory process, as IL-1β, TNF-α and IL-6 (p < 0.05 all), compared with healthy individuals, which can be the trigger to insulin resistance in this population.ConclusionIndividuals with FPLD besides having typical dysfunctions of metabolic syndrome, show a hyperactivation of ERS associated with increased systemic inflammatory profile, which together may explain the complex clinical aspect of this diseases.Trial registration HCRP no 6711/2012.

Project description:Background:Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods:We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results:Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions:Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

Dataset Information

A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features.

Publications

A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features.

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