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The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is essential for placental development, and alterations in its expression and/or activity are associated with human placental pathologies such as pre-eclampsia or IUGR. However, the molecular regulation of PPARG in cytotrophoblast differentiation and in the underlying mesenchyme remains poorly understood. Our main goal was to study the impact of mutations in the ligand-binding domain (LBD) of the PPARG gene on cytotrophoblast fusion (PPARG E352Q ) and on fibroblast cell migration (PPARG R262G /PPARG L319X ). Our results showed that, compared to cells with reconstituted PPARG WT , transfection with PPARG E352Q led to significantly lower PPARG activity and lower restoration of trophoblast fusion. Likewise, compared to PPARG WT fibroblasts, PPARG R262G /PPARG L319X fibroblasts demonstrated significantly inhibited cell migration. In conclusion, we report that single missense or nonsense mutations in the LBD of PPARG significantly inhibit cell fusion and migration processes., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Aims: Mutations of the LMNA gene encoding lamin A/C induce heterogeneous phenotypes ranging from cardiopathies and myopathies to lipodystrophies. The aim of this study was to compare cardiometabolic complications in patients with heterozygous LMNA mutations at the 482nd codon, the 'hotspot' for partial lipodystrophy, with carriers of other, non-R482 LMNA mutations., Methods and Results: This study included 29 patients with R482 LMNA mutations, 29 carriers of non-R482 LMNA mutation and 19 control subjects. Cardiac and metabolic phenotypes were compared between groups. A family history of either cardiac implantable electronic devices (CIEDs; P <  0.001) or sudden death (P <  0.01) was more frequent in non-R482 than R482 carriers. The non-R482 carriers also had more abnormalities on electrocardiography and received CIEDs more often than R482 carriers (P <  0.001). On cardiac ultrasound, non-R482 patients had greater frequencies of left atrial enlargement (P <  0.05) and lower left ventricular ejection fractions (P <  0.01) than R482 carriers. In contrast, R482 carriers had lower BMI (P <  0.05), leptin (P <  0.01) and fat mass (P <  0.001), but higher intra-/total abdominal fat-mass ratios (P <  0.001) and prevalences of diabetes (P <  0.01) and hypertriglyceridaemia (P <  0.05) than non-R482 carriers, with a trend towards more coronary artery disease. However, non-R482 carriers had higher intra-/total abdominal fat-mass ratios (P <  0.02) and prevalences of diabetes (P <  0.001) and hypertriglyceridaemia (P <  0.05) than the controls., Conclusion: Non-R482 carriers present more frequently with arrhythmias than R482 carriers, who twice as often have diabetes, suggesting that follow-up for laminopathies could be adjusted for genotype. Non-R482 mutations require ultra-specialized cardiac follow-up, and coronary artery disease should not be overlooked. Although overlapping phenotypes are found, LMNA mutations essentially lead to tissue-specific diseases, favouring genotype-specific pathophysiological mechanisms., (Copyright © 2018. Published by Elsevier Masson SAS.)

Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure. Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.

A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient's skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts were transfected with a construct carrying the patient's mutation; R388P-lamin A (LA) predominantly accumulated within the nucleoplasm and was depleted at the nuclear periphery, altering the anchorage of the inner nuclear membrane protein emerin and the nucleoplasmic protein LAP2-alpha. The mutant LA triggered a frequent and severe nuclear dysmorphy that occurred independently of prelamin A processing, as well as increased histone H3K9 acetylation. Nuclear dysmorphy was not significantly improved when transfected cells were treated with drugs disrupting microtubules or actin filaments or modifying the global histone acetylation pattern. Therefore, releasing any force exerted at the nuclear envelope by the cytoskeleton or chromatin did not rescue nuclear shape, in contrast to what was previously shown in Hutchinson-Gilford progeria due to other LMNA mutations. Our results point to the specific cytotoxic effect of the R388P-lamin A mutant, which is clinically related to a rare and severe multisystemic laminopathy phenotype., Competing Interests: The authors have declared that no competing interests exist.

Background: Some LMNA mutations responsible for lipodystrophies, and some HIV-protease inhibitors (PIs) induce accumulation of farnesylated prelamin A and premature senescence in some cell types. Patients with LMNA mutations or under PI-based therapy suffer from early atherosclerosis. The metalloprotease ZMPSTE24 is the key enzyme in prelamin A maturation., Aim: We studied whether altered expression of ZMPSTE24 could contribute to vascular cell dysfunction in response to LMNA mutations or PI treatments., Methods: Protein expression of prelamin A and ZMPSTE24 were evaluated in patients' cells and in human cultured VSMCs. Oxidative stress, inflammation, senescence and transdifferentiation/calcification were evaluated in VSMCs., Results: Fibroblasts from LMNA-mutated lipodystrophic patients (mutations R482W, D47Y or R133L) and peripheral blood mononuclear cells from PI-treated-HIV-infected patients expressed increased prelamin A and decreased ZMPSTE24, which was also observed in VSMCs overexpressing mutant LMNA or treated with PIs. These alterations correlated with oxidative stress, inflammation, senescence and calcification (all p < 0.05). ZMPSTE24 silencing in native VSMCs recapitulated the mutant LMNA- and PI-induced accumulation of farnesylated prelamin A, oxidative stress, inflammation, senescence and calcification. A negative regulator of ZMPSTE24, miRNA-141-3p, was enhanced in LMNA-mutated or PI-treated VSMCs. The farnesylation inhibitors pravastatin and FTI-277, or the antioxidant N-acetyl cysteine, partly restored ZMPSTE24 expression, and concomitantly decreased oxidative stress, inflammation, senescence, and calcification of PI-treated VSCMs., Conclusions: ZMPSTE24 downregulation is a major contributor in VSMC dysfunctions resulting from LMNA mutations or PI treatments that could translate in early atherosclerosis at the clinical level. These novel pathophysiological mechanisms could open new therapeutic perspectives for cardiovascular aging., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Laminopathies are associated with a broad spectrum of clinical manifestations, from lipodystrophy to cardiac diseases. The purpose of this study was to assess genotype-phenotype correlations in a lipodystrophic laminopathy caused by the Lamin A (LMNA) mutation T655fsX49. This mutation leads to synthesis of nonfarnesylated-mutated prelamin A that does not undergo the physiologic lamin A maturation process., Methods and Results: We studied 35 patients originating from Reunion Island who carried the LMNA T655fsX49 mutation. Comparisons of cardiac and endocrinologic features were made between homozygous and heterozygous patients. Homozygous patients presented more overlapping syndromes with severe cardiac phenotypes, defined by cardiolaminopathy, early atheroma with coronary heart disease (CHD) and high-degree conduction disorder compared with heterozygous (40% vs 4%; P = .016). Moreover, homozygous patients had earlier onset (49.6 vs 66 years old; P = .0002). Left ventricle lowered ejection fraction associated with heart failure was more frequent in homozygous than in heterozygous patients (40% vs 0%, respectively). Lipodystrophic traits were more marked in the homozygous group but only reached statistical significance for L4 subcutaneous fat measurement (2.8 ± 2.16 vs 18.7 ± 8.9 mm; P = .008) and leptin levels (2.45 ± 1.6 vs 11.26 ± 7.2 ng/mL; P = .0001)., Conclusions: Our results suggest that there is a relationship between mutated prelamin-A accumulation and the severity of the phenotypes in homozygous familial partial lipodystrophy type 2 patients who harbor the LMNA T655fsX49 mutation. A dose-dependent effect seems likely., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The nuclear lamina is implicated in the regulation of various nuclear functions. Several laminopathy-causing mutations in the LMNA gene, notably the p.R482W substitution linked to familial partial lipodystrophy type 2 (FPLD2), are clustered in the immunoglobulin fold of lamin A. We report a functional association between lamin A and fragile X-related protein 1 (FXR1P), a protein of the fragile X-related family involved in fragile X syndrome. Searching for proteins differentially interacting with the immunoglobulin fold of wild-type and R482W mutant lamin A, we identify FXR1P as a novel component of the lamin A protein network. The p.R482W mutation abrogates interaction of FXR1P with lamin A. Fibroblasts from FPLD2 patients display elevated levels of FXR1P and delocalized FXR1P. In human adipocyte progenitors, deregulation of lamin A expression leads to FXR1P up-regulation, impairment of adipogenic differentiation and induction of myogenin expression. FXR1P overexpression also stimulates a myogenic gene expression program in these cells. Our results demonstrate a cross-talk between proteins hitherto implicated in two distinct mesodermal pathologies. We propose a model where the FPLD2 lamin A p.R482W mutation elicits, through up-regulation of FXR1P, a remodeling of an adipogenic differentiation program into a myogenic program.

Objective: Some mutations in LMNA, encoding A-type lamins, are responsible for Dunnigan-type-familial partial lipodystrophy (FPLD2), with altered fat distribution and metabolism. The high prevalence of early and severe cardiovascular outcomes in these patients suggests that, in addition to metabolic risk factors, FPLD2-associated LMNA mutations could have a direct role on the vascular wall cells., Approach and Results: We analyzed the cardiovascular phenotype of 19 FPLD2 patients aged >30 years with LMNA p.R482 heterozygous substitutions, and the effects of p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. In 68% of FPLD2 patients, early atherosclerosis was attested by clinical cardiovascular events, occurring before the age of 45 in most cases. In transduced endothelial cells, exogenous wild-type-prelamin-A was correctly processed and localized, whereas p.R482W-prelamin-A accumulated abnormally at the nuclear envelope. Patients' fibroblasts also showed a predominant nuclear envelope distribution with a decreased rate of prelamin-A maturation. Only p.R482W-prelamin-A induced endothelial dysfunction, with decreased production of NO, increased endothelial adhesion of peripheral blood mononuclear cells, and cellular senescence. p.R482W-prelamin-A also induced oxidative stress, DNA damages, and inflammation. These alterations were prevented by treatment of endothelial cells with pravastatin, which inhibits prelamin-A farnesylation, or with antioxidants. In addition, pravastatin allowed the correct relocalization of p.R482W-prelamin-A within the endothelial cell nucleus. These data suggest that farnesylated p.R482W-prelamin-A accumulation at the nuclear envelope is a toxic event, leading to cellular oxidative stress and endothelial dysfunction., Conclusions: LMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patients' early atherosclerosis.

Background: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase., Methods: We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied., Results: Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence., Conclusions: We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.

Objective: Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular renin-angiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ. Approach and Results- We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II-mediated mitogen-activated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes., Conclusions: Two novel FPLD3-linked PPARG mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension.

Some LMNA mutations responsible for insulin-resistant lipodystrophic syndromes are associated with peripheral subcutaneous lipoatrophy and faciocervical fat accumulation. Their pathophysiologic characteristics are unknown. We compared histologic, immunohistologic, ultrastructural, and protein expression features of enlarged cervical subcutaneous adipose tissue (scAT) obtained during plastic surgery from four patients with LMNA p.R482W, p.R439C, or p.H506D mutations versus cervical fat from eight control subjects, buffalo humps from five patients with HIV infection treated or not with protease inhibitors, and dorsocervical lipomas from two patients with mitochondrial DNA mutations. LMNA-mutated cervical scAT and HIV-related buffalo humps were dystrophic, with an increased percentage of small adipocytes, increased fibrosis without inflammatory features, and decreased number of blood vessels, as compared with control samples. Samples from patients with LMNA mutations or protease inhibitor-based therapy demonstrated accumulation of prelamin A, altered expression of adipogenic proteins and brown fat-like features, with an increased number of mitochondria and overexpression of uncoupling protein 1 (UCP1). These features were absent in samples from control subjects and from patients with HIV not treated with protease inhibitors. Mitochondrial DNA-mutated cervical lipomas demonstrated inflammatory fibrosis with distinct mitochondrial abnormalities but neither UCP1 expression nor prelamin A accumulation. In conclusion, Enlarged cervical scAT from patients with lipodystrophy demonstrated small adipocytes, fibrosis, and decreased vessel numbers. However, only cervical fat from patients with LMNA mutations or who had received protease inhibitor therapy accumulated prelamin A and exhibited similar remodeling toward a brown-like phenotype with UCP1 overexpression and mitochondrial alterations., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications.

Objective To describe new data about the wide phenotypic variability of diseases due to mutations in the lamin A/C gene (LMNA). Design We report a complex phenotype in a patient with familial partial lipodystrophy of the Dunnigan type (FPLD) and study the frequency of her unusual clinical signs in 19 other LMNA-mutated lipodystrophic patients from 8 different families and 14 non-mutated family members. Case Report The patient was diagnosed with FPLD due to the R482W LMNA mutation after familial screening. Surprisingly, she had no biological signs of insulin resistance. The presence of hypertension with hypokalaemia led to the diagnosis of primary hyperaldosteronism. Thyroid investigations showed a euthyroid multinodular goiter. In addition, the patient exhibited a juvenile akineto-hypertonic syndrome. Results Goiter was identified with a similar frequency (55%) in LMNA-mutated lipodystrophic patients (11 out of 20, originating from 5 families among 8) compared to non-mutated family controls (35%; 5 patients out of 14, all originating from the same family). No case of primary hyperaldosteronism or extrapyramidal syndrome was identified in other studied subjects, either LMNA-mutated or not. Conclusions This R482W-LMNA mutated patient showed an association of features (primary hyperaldosteronism, euthyroid goiter and extra-pyramidal syndrome, raising the question of a link with her laminopathy. Prevalence of goiter tended to be higher in LMNA-mutated than in non-mutated subjects. Hyperaldosteronism seems coincidental. Although extrapyramidal syndrome has never been reported in lipodystrophic patients, it may nevertheless be linked to the LMNA mutation since multiple neurological features have been associated with alterations in lamins A/C.

Laminopathies are a group of diseases due to mutations of type A-lamins, a group of proteins lining the inner aspect of cell nuclei. These diseases illustrate the complexity of the genotype-phenotype relationship characteristic of same genetic diseases. Since the discovery of the causal role of LMNA gene mutations in the genesis of Emery Dreifuss muscular dystrophy in 1999, no less than eight other diseases have been associated with mutations of this same gene! The tissue-specific nature of the clinical manifestations, contrasting with the ubiquitous expression of these proteins, has incited much research concerning the physiological role of lamins, considered to be much broader than the structural function initially put forward. Certain laminopathies, which combine insulin resistance, android distribution of adipose tissue, dyslipidemia, early atherosclerosis, and hepatic steatosis, appear very similar though more severe to the frequent dysmetabolism syndrome. The relationships of laminopathies with accelerated aging syndrome, Hutchinson-Gilford progeria, or progeroid syndromes, which are also related to A/C lamin anomalies, could provide new avenues of research on the pathogenesis of the metabolic syndrome. In addition, clinicians have to be aware of atypical and milder forms of laminopathies, that require specific investigations and molecular screening of relatives allowing an adequate medical management.

Diseases due to mutations in the lamin A/C gene (LMNA) are highly heterogeneous, including neuromuscular and cardiac dystrophies, lipodystrophies, and premature ageing syndromes. In this study we characterized the neuromuscular and cardiac phenotypes of patients bearing the heterozygous LMNA R482W mutation, which is the most frequent genotype associated with the familial partial lipodystrophy of the Dunnigan type (FPLD). Fourteen patients from two unrelated families, including 10 affected subjects, were studied. The two probands had been referred for lipoatrophy and/or diabetes. Lipodystrophy, exclusively observed in LMNA-mutated patients, was of variable severity and limited to postpubertal subjects. Lipodystrophy and metabolic disturbances were more severe in women, even if an enlarged neck was a constant finding. The severity of hypertriglyceridemia and hirsutism in females was related to that of insulin resistance. Clinical muscular alterations were only present in LMNA-mutated patients. Clinical and histological examination showed an invalidating, progressive limb-girdle muscular dystrophy in a 42-yr-old woman that had been present since childhood, associated with a typical postpubertal FPLD phenotype. Six of eight adults presented the association of calf hypertrophy, perihumeral muscular atrophy, and a rolling gait due to proximal lower limb weakness. Muscular histology was compatible with muscular dystrophy in one of them and/or showed a nonspecific excess of lipid droplets (in three cases). Immunostaining of lamin A/C was normal in the six muscular biopsies. Surprisingly, calpain 3 expression was undetectable in the patient with the severe limb-girdle muscular dystrophy, although the gene did not reveal any molecular alterations. At the cardiac level, cardiac septal hypertrophy and atherosclerosis were frequent in FPLD patients. In addition, a 24-yr-old FPLD patient had a symptomatic second degree atrioventricular block. In conclusion, we showed that most lipodystrophic patients affected by the FPLD-linked LMNA R482W mutation show muscular and cardiac abnormalities. The occurrence and severity of the myopathic and lipoatrophic phenotypes varied and were not related. The muscular phenotype was evocative of limb girdle muscular dystrophy. Cardiac hypertrophy and advanced atherosclerosis were frequent. FPLD patients should receive careful neuromuscular and cardiac examination whatever the underlying LMNA mutation.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.

A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.

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.