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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with Dunnigan-type familial partial lipodystrophy (FPLD) are born with normal fat distribution, but after puberty experience regional and progressive adipocyte degeneration, often associated with profound insulin resistance and diabetes. Recently, the FPLD gene was mapped to chromosome 1q21-22, which harbours the LMNA gene encoding nuclear lamins A and C. Mutations in LMNA were shown to underlie autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD), which is characterized by regional and progressive skeletal muscle wasting and cardiac effects. We hypothesized that the analogy between the regional muscle wasting in EDMD-AD and the regional adipocyte degeneration in FPLD, in addition to its chromosomal localization, made LMNA a good candidate gene for FPLD. DNA sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel missense mutation, R482Q, which co-segregated with the FPLD phenotype and was absent from 2000 normal alleles ( P = 1.1 x 10(-13)). This is the first report of a mutation underlying a degenerative disorder of adipose tissue and suggests that LMNA mutations could underlie other diseases characterized by tissue type- and anatomical site-specific cellular degeneration.
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PMID:Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. 1058 85

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
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PMID:Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. 1081 87

Emery-Dreifuss muscular dystrophy (EDMD) was delineated as a separate form of muscular dystrophy nearly 40 years ago, based on the distinctive clinical features of early contractures and humero-peroneal weakness, and cardiac conduction defects. The gene, STA at Xq28, for the commoner X-linked EDMD encodes a 34 kD nuclear membrane protein designated 'emerin', and in almost all cases on immunostaining is absent in muscle, skin fibroblasts, leucocytes and even exfoliative buccal cells, and a mosaic pattern in female carriers. The gene, LMNA at 1q21, for the autosomal dominant Emery-Dreifuss muscular dystrophy encodes other nuclear membrane proteins, lamins A/C. The diagnosis (at present) depends on mutation analysis rather than protein immunohistochemistry. It is still not at all clear how defects in these nuclear membrane proteins are related to the phenotype, even less clear that LMNA mutations can also be associated with familial dilated cardiomyopathy with no weakness, and even familial partial lipodystrophy with diabetes mellitus and coronary heart disease! What began as clinical studies in a relatively rare form of dystrophy has progressed to detailed research into the functions of nuclear membrane proteins particularly in regard to various forms of heart disease.
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PMID:Emery-Dreifuss muscular dystrophy - a 40 year retrospective. 1083 46

We previously identified a novel mutation, namely LMNA R482Q, that was found to underlie Dunnigan-type partial lipodystrophy (FPLD) and diabetes in an extended Canadian kindred. We have since sequenced LMNA in five additional Canadian FPLD probands and herein report three new rare missense mutations in LMNA: V440M, R482W, and R584H. One severely affected subject was a compound heterozygote for both V440M and R482Q. The findings indicated that 1) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not lamin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence that is specific for lamin A; 3) the V440M mutation may not cause lipodystrophy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipodystrophy; and 5) variation in the severity of the phenotype might be related to environmental factors.
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PMID:Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy. 1099 45

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.
Diabetes 2000 Nov
PMID:Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy. 1107 66

The common syndrome of insulin resistance is frequently seen in obese individuals, and is characterized by glucose intolerance, dyslipidemia, high blood pressure, and an increased risk of coronary heart disease. A rare genetic form of insulin resistance is Dunnigan-type familial partial lipodystrophy (FPLD; OMIM #151660), which is characterized by loss of subcutaneous fat from extremities, trunk, and gluteal region, and always by insulin resistance and hyperinsulinemia, often with hypertension, dyslipidemia, type-2 diabetes and early endpoints of atherosclerosis. FPLD was recently discovered to result from mutated LMNA (R482Q; OMIM #150330.0010), which is the gene encoding nuclear lamins A and C. Results from extended pedigrees indicate that dyslipidemia precedes the plasma glucose abnormalities in FPLD subjects with mutant LMNA, and that the hyperinsulinemia is present early in the course of the disease. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. Thus, rare mutations in a nuclear structural protein can be associated with markedly abnormal qualitative and quantitative phenotypes, indicating that a defect in the structure and function of the nuclear envelope can result in a phenotype that shares many aspects with the common syndrome of insulin resistance.
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PMID:Insulin resistance in human partial lipodystrophy. 1112 71

Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) is a rare monogenic form of insulin resistance characterized by loss of subcutaneous fat from the extremities, trunk, and gluteal region. FPLD recapitulates the main metabolic attributes of the insulin resistance syndrome, including central obesity, hyperinsulinemia, glucose intolerance and diabetes, dyslipidemia, and hypertension. Through the use of focused DNA sequencing of positional candidate genes on chromosome 1q21, we discovered that FPLD results from mutations in LMNA (R482Q; OMIM 150330.0010), which is the gene that encodes nuclear lamins A and C. By stratifying members of extended FPLD pedigrees according to LMNA genotype, we found that hyperinsulinemia is present early in the course of the disease and that dyslipidemia (characterized by high triglycerides and depressed HDL cholesterol) precedes the development of glucose abnormalities. Plasma leptin is also markedly reduced in subjects with FPLD due to mutant LMNA. The findings in FPLD indicate that defective structure of the nuclear envelope produces a phenotype of insulin resistance. The findings may have relevance for common insulin resistance and for drug-associated lipodystrophies, whose molecular basis is unknown at present.
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PMID:Familial partial lipodystrophy: a monogenic form of the insulin resistance syndrome. 1113 44

Lipodystrophy is characterized by altered partition of adipose tissue. Despite heterogeneous causes, which include genetic, autoimmune and drug-induced forms, lipodystrophy syndromes have similar metabolic attributes, including insulin resistance, hyperlipidemia and diabetes. The mechanisms underlying the insulin resistance are unknown. One form of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD) was shown to result from mutations in the LMNA gene, which encodes nuclear lamins A and C. Although the relationship between the mutations in the nuclear envelope and insulin resistance is unclear at present, these findings might eventually be shown to have relevance for the common insulin resistance syndrome and for drug-associated lipodystrophies.
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PMID:Molecular basis of partial lipodystrophy and prospects for therapy. 1128 83

Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg(482)Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.
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PMID:Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene. 1134 41

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. The LMNA gene encoding two nuclear envelope proteins (lamins A and C [lamin A/C]) maps to chromosome 1q21 and has been associated with five distinct pathologies, including Dunnigan-type familial partial lipodystrophy, a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes. Since patients with MAD frequently have partial lipodystrophy and insulin resistance, we hypothesized that the disease may be caused by mutations in the LMNA gene. We analyzed five consanguineous Italian families and demonstrated linkage of MAD to chromosome 1q21, by use of homozygosity mapping. We then sequenced the LMNA gene and identified a homozygous missense mutation (R527H) that was shared by all affected patients. Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation.
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PMID:Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. 1278 12


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