Familial partial lipodystrophy complicated by pre-eclampsia.
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Adult↗
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Results for “Lipodystrophy, Familial Partial”
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Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy.
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.
DNA↗
Effectiveness of gastric bypass surgery in a patient with familial partial lipodystrophy.
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Body Weight↗
[Mutations of the lamin A/C gene causing familial partial lipodystrophy: significance for the development of hyperlipidemia and insulin resistant diabetes mellitus].
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Amino Acid Substitution↗
Familial partial lipodystrophy.
The lipodystrophies are rare disorders characterized by insulin resistance and the absence or loss of body fat. The 4 subtypes of lipodystrophy are characterized by onset and distribution. Partial lipodystrophy is rare, with loss of fat from the extremities and excess fat accumulation in the face and neck; recognizing this phenotype and subsequent referral for endocrinologic care may improve outcome and reduce mortality.
Acanthosis Nigricans↗
Common genomic variation in LMNA modulates indexes of obesity in Inuit.
We discovered that rare mutations in LMNA, which encodes lamins A and C, underlie autosomal dominant Dunnigan-type familial partial lipodystrophy. Because familial partial lipodystrophy is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes. We subsequently discovered a common single nucleotide polymorphism (SNP) in LMNA, namely 1908C/T, which was associated with obesity-related traits in Canadian Oji-Cree. We now report association of this LMNA SNP with anthropometric indexes in 186 nondiabetic Canadian Inuit. We found that physical indexes of obesity, such as body mass index, waist circumference, waist to hip circumference ratio, subscapular skinfold thickness, and subscapular to triceps skinfold thickness ratio were each significantly higher among Inuit subjects with the LMNA 1908T allele than in subjects with the 1908C/1908C genotype. For each significantly associated obesity-related trait, the LMNA 1908C/T SNP genotype accounted for between approximately 10--100% of the attributable variation. The results indicate that common genetic variation in LMNA is an important determinant of obesity-related quantitative traits.
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Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy.
Familial partial lipodystrophy (FPL) and lipodystrophy observed in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) share multiple clinical and metabolic features. Recently, missense mutations of LMNA encoding lamin A/C have been described in FPL providing evidence for a pivotal role of lamin A/C in the regulation of adipocytes. Moreover, the cellular retinoic acid binding protein (CRABP) has been suggested to be involved in HAART associated lipodystrophy. In this study, we excluded mutations within the complete coding region and the promoter of LMNA and the CRABP II gene in HIV-1 infected patients with lipodystrophy and also any correlation of the nucleotide polymorphism at codon 566 in exon 10 of LMNA with metabolic abnormalities. Protease inhibitors including indinavir have been shown to reduce adipocyte cell differentiation and increase apoptosis of adipocytes in vitro. Indinavir leads to altered retinoic acid signaling most likely by an activation of the RAR/RXR heterodimer, perhaps by displacing all-trans-retinoic acid from CRABP. Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter. This results in altered LMNA expression and subsequent impaired adipocyte differentiation, lipodystrophic body habitus, and metabolic disturbances in HIV infected patients receiving HAART.
Amino Acid Sequence↗
Elevated serum C-reactive protein and free fatty acids among nondiabetic carriers of missense mutations in the gene encoding lamin A/C (LMNA) with partial lipodystrophy.
OBJECTIVE: Dunnigan-type familial partial lipodystrophy (FPLD) due to mutant LMNA is a monogenic form of insulin resistance. Affected subjects, especially women, are at increased risk of early coronary heart disease (CHD). Although common insulin resistance is associated with several biochemical perturbations, including elevated C-reactive protein (CRP), the biochemical profile in subjects with mutant LMNA is incompletely defined. METHODS AND RESULTS: We studied 35 nondiabetic adult FPLD subjects (of whom 24 were women) with either the LMNA R482Q or R482W missense mutations and 51 matched normal first-degree relatives (of whom 27 were women). Compared with normal controls, LMNA mutation carriers had significantly higher plasma insulin and more dyslipidemia, higher mean triglycerides and lower HDL cholesterol, significantly higher nonesterified free fatty acids and CRP, and significantly lower leptin and adiponectin than controls. Subgroup analyses showed that these differences were more pronounced in women. Other biomarkers such as resistin, fibrinogen, and plasminogen activator inhibitor-1 were not different between groups. CONCLUSIONS: LMNA mutations in nondiabetic patients with FPLD are associated with several metabolic and biochemical changes, particularly in women. The unfavorable profile might contribute to the increased susceptibility to CHD seen in LMNA mutation carriers.
Adult↗
Partial lipodystrophy and familial C3 deficiency.
A familial deficiency of C3 in the family of a patient with partial lipodystrophy is reported for the first time. This genetic defect is termed hypomorphism of C3 fast (C3f). The defect is detected by analysis of C3 phenotype by densitometry and crossed gel-immunoelectrophoresis; all affected individuals have had reduced serum C3 (lower than 2 SD below mean) on at least one occasion. The possibility that partial lipodystrophy and the frequently associated glomerulonephritis occur in immunologically deficient individuals is supported by this observation.
Complement C3↗
Monogenic disorders of obesity and body fat distribution.
Recently, great progress has been made towards understanding the molecular basis of body fat regulation. Identification of mutations in several genes in spontaneous monogenic animal models of obesity and development of transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) gamma2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic body fat disorders may lead to better treatment and prevention of obesity and other disorders of adipose tissue in the future.
Adipose Tissue↗
Confirmation of linkage of hereditary partial lipodystrophy to chromosome 1q21-22.
Familial lipodystrophy is a genetically heterogeneous set of disorders characterized by a total or partial absence of subcutaneous fat, diabetes mellitus or impaired glucose tolerance, hyperlipidemia, and hypermetabolism [Senior and Gellis, 1964]. One subtype, familial partial lipodystrophy Dunnigan (FPLD), is a rare autosomal dominant trait that results in an gradual loss of subcutaneous fat in the lower trunk and limbs, Type V hyperlipoproteinemia, hypertriglyceridemia, and insulin-resistant diabetes. Previous reports of this condition have been limited to case reports or very small families. Recently, Peters et al. reported on linkage of five families of Western European descent to a 5.3 cM region on chromosome 1q21-22 between the flanking markers D1S305 and D1S1600 [Peters et al., 1998: Nat Genet 18:292-295]. We performed linkage and haplotype analysis using highly polymorphic, microsatellite markers on a large, multigeneration Caucasian kindred of German ancestry. The maximum two-point lod score achieved was 4.96 at theta(max) = 0 for marker D1S2721. Multipoint analysis gave an overall maximum lod score of 6.27 near marker D1S2721. The results of the haplotype analysis support the minimal candidate region as reported by Peters et al.
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Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene.
Mutations in different domains of the LMNA (lamin A/C) gene encoding nuclear envelope proteins lamin A and lamin C cause familial partial lipodystrophy (Dunnigan variety), dilated cardiomyopathy, and autosomal dominant forms of Emery-Dreifuss and limb-girdle muscular dystrophies. The objective of this study was to evaluate LMNA variants in two families with familial partial lipodystrophy (Dunnigan variety) who also had cardiac conduction system defects and other manifestations related to cardiomyopathy. We performed mutational analysis of the lamin A/C gene in affected and unaffected subjects by deoxyribonucleic acid sequencing of the exons. Two novel missense mutations were identified in exon 1 of the lamin A/C gene. One mutation, R28W (CGG-->TGG), affected the amino-terminal head domain, and the other, R62G (CGC-->GGC), affected the alpha-helical rod domain. Affected subjects from both families had an increased prevalence of cardiac manifestations, such as atrioventricular conduction defects, atrial fibrillation, and heart failure due to ventricular dilatation, as well as pacemaker implantation. The proband from one of the families also had proximal muscle weakness. Novel genetic defects in the LMNA gene in two families with the Dunnigan variety of familial partial lipodystrophy, cardiac conduction system defects, and other manifestations related to cardiomyopathy suggest the occurrence of a multisystem dystrophy syndrome due to LMNA mutations.
Adult↗
Lipodystrophies.
The lipodystrophies are rare disorders characterized by selective but variable loss of adipose tissue. Metabolic complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, and fatty liver, increase in severity with the extent of fat loss. The lipodystrophies can be classified into two major types: familial and acquired. The main subtypes of familial lipodystrophies are congenital generalized lipodystrophy, an autosomal recessive disorder characterized by near complete lack of metabolically active adipose tissue from birth, and familial partial lipodystrophy, Dunnigan type, an autosomal dominant disorder characterized by loss of subcutaneous fat from the extremities at puberty and excess fat accumulation in the face and neck. Recently, a gene for congenital generalized lipodystrophy was localized to chromosome 9q34, and a gene for familial partial lipodystrophy, Dunnigan type, to chromosome 1q21-22; the genes, however, remain to be identified. Patients with acquired generalized lipodystrophy have generalized loss of subcutaneous fat, but those with acquired partial lipodystrophy have fat loss limited to the face, trunk, and upper extremities. Both varieties occur approximately three times more often in women, begin during childhood, and have underlying autoimmunity. Patients infected with the human immunodeficiency virus (HIV) who are receiving therapy that includes HIV-1 protease inhibitors have been reported to develop a lipodystrophy characterized by loss of subcutaneous fat from the extremities and face but excess fat deposition in the neck and trunk. Localized lipodystrophies can be caused by drugs, pressure, panniculitis, or unknown mechanisms. Current management of patients includes cosmetic surgery, diet, and drug therapy for control of diabetes and dyslipidemia.
Adipose Tissue↗
Nuclear envelope proteins and associated diseases.
There is a growing body of evidence in favour of the presence of human diseases caused by mutations in genes that encode the nuclear envelope proteins emerin and lamin A/C (lamin A and C are alternatively spliced variants of the same gene). Emerin deficiency results in X-linked Emery-Dreifuss muscular dystrophy (EDMD). Lamin A/C mutations cause the autosomal-dominant form of EDMD, limb-girdle muscular dystrophy with atrioventricular conduction disturbances (type 1B), hypertrophic cardiomyopathy and Dunnigan-type familial partial lipodystrophy. In the targeted mouse model of lamin A gene deficiency, loss of lamin A/C is associated with mislocalization of emerin. Thus, one plausible pathomechanism for EDMD, limb-girdle muscular dystrophy type 1B, hypertrophic cardiomyopathy and familial partial lipodystrophy is the presence of specific abnormalities of the nuclear envelope. Therefore, a group of markedly heterogeneous disorders can be classified as 'nuclear envelopathies'. The present review summarizes recent findings on nuclear envelope proteins and diseases.
Animals↗
Laminopathies and atherosclerosis.
Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and Hutchinson-Gilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases FPLD2 and HGPS are more likely to provide clues about new pathways for the general process of atherosclerosis. Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome are laminopathies caused by mutation in LMNA that feature atherosclerosis, which is related to proatherogenic metabolic disturbances and to the generalized process of accelerated aging, respectively. These monogenic diseases may provide clues about new pathways for atherogenesis.
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Molecular basis of partial lipodystrophy and prospects for therapy.
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.
Endopeptidases↗
The molecular basis of genetic lipodystrophies.
OBJECTIVES: Hyperinsulinemia is often associated with a cluster of metabolic abnormalities, which usually presents before the onset of frank diabetes. Lipodystrophy syndromes are frequently associated with hyperinsulinemia and may act as models for insulin resistance. Lipodystrophy is characterized in broad terms by loss of subcutaneous adipose tissue. Despite heterogeneous causes, which include both genetic and acquired forms, lipodystrophy syndromes have similar metabolic attributes, including insulin resistance, hyperlipidemia and diabetes. RESULTS: Recently, the molecular basis of two genetic forms of lipodystrophy, namely Dunnigan-type familial partial lipodystrophy (FPLD; MIM 151660) and Berardinelli-Seip complete lipodystrophy (BSCL; MIM 269700) have been reported. There is evidence for genetic heterogeneity for both types of lipodystrophy. In addition, murine models of lipodystrophy have provided key insights into alterations of metabolic pathways in lipodystrophy. CONCLUSIONS: Delineation of the human molecular genetic basis of two distinct forms of inherited lipodystrophy may have relevance for the common insulin resistance syndrome and for acquired lipodystrophy syndromes.
Adipose Tissue↗
Lessons from human mutations in PPARgamma.
Familial partial lipodystrophy (FPLD) is characterized by adipose tissue repartitioning with multiple metabolic disturbances, including insulin resistance and dyslipidemia. Classical FPLD results from mutations in LMNA encoding nuclear lamin A/C (FPLD2), but recently some families with partial lipodystrophy and normal LMNA sequence were found to have germline mutations in PPARgamma (FPLD3). For instance, all four affected subjects in a three-generation Canadian FPLD3 kindred ascertained based upon a clinical diagnosis of partial lipodystrophy were heterozygous for the PPARgamma F388L mutation, which altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPARgamma. The mutation was absent from normal subjects, and functional studies showed that the mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by rosiglitazone, with no evidence of a dominant-negative mechanism. Other reported FPLD3 patients with mutant PPARgamma were ascertained either directly based on a clinical diagnosis of lipodystrophy (R425C mutation), or based on insulin resistance with subsequent demonstration of lipodystrophy (V290M and P467L mutations). Compared to subjects with mutant LMNA, lipodystrophic subjects with mutant PPARgamma had less severe adipose involvement, together with more severe clinical and biochemical manifestations of insulin resistance, and more variable response to treatment with thiazolidinediones. Thus, rare natural mutations affecting PPARgamma ligand binding and/or transactivation functions cause partial lipodystrophy, with associated components that resemble the metabolic syndrome.
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