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C Vigouroux

Publications and source records attributed to C Vigouroux.

At least 19 recordsLinked to original sources
PubMed2005

[Laminopathies: lipodystrophies, insulin resistance, syndromes of accelerated ageing... and others].

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.

Aging, Premature↗
PubMed2005

Etiological investigations in apparent type 2 diabetes: when to search for lamin A/C mutations?

Prevalence of diabetes is increasing worldwide in epidemic proportions. Its appropriate clinical management requires a careful etiological diagnosis. Laminopathies recently emerged as clinically heterogeneous genetic disorders due to mutations in lamins or lamin-associated proteins, which are components of the nuclear envelope. Laminopathies regroup at least eight distinct diseases, belonging to the groups of skeletal and/or cardiac muscular dystrophies, axonal neuropathies, premature ageing syndromes and familial lipodystrophies, all resulting from alterations in LMNA, encoding type A-lamins. Pathophysiological mechanisms explaining how mutations in an unique gene could lead to such various phenotypes are still unknown, but probably involve alterations in cellular mechanical stress responses, in gene expression, and/or in post-translational maturation of lamin A. Familial Partial Lipodystrophy of the Dunnigan type (FPLD2), with specific features of pseudo-cushingoid lipodystrophy, marked insulin resistance and muscular hypertrophy, and a relatively homogeneous genotype, was thought, until recently, to be the only laminopathy causing diabetes. However, recent studies have revealed that insulin resistance and diabetes could be key features of attenuated or more complex phenotypes of laminopathy. In the light of these recent findings, this review will describe the clinical, morphological and biological features that should lead clinicians to consider the diagnosis of laminopathy in a diabetic patient. The recognition of such an etiology for diabetes is important not only for its appropriate medical treatment, but also because specific investigations are required to detect possible asymptomatic life-threatening complications. In addition, the molecular screening of family members allows an earlier efficient clinical management of affected relatives.

Diabetes Mellitus, Type 2↗
PubMed2005

Diseases of adipose tissue: genetic and acquired lipodystrophies.

Human lipodystrophies represent a group of diseases characterized by altered body fat amount and/or repartition and major metabolic alterations with insulin resistance leading to diabetic complications and increased cardiovascular and hepatic risk. Genetic forms of lipodystrophies are rare. Congenital generalized lipodystrophy or Berardinelli-Seip syndrome, autosomal recessive, is characterized by a complete early lipoatrophy and severe insulin resistance and results, in most cases, from mutations either in the seipin gene of unknown function or AGPAT2 encoding an enzyme involved in triacylglycerol synthesis. The Dunnigan syndrome [FPLD2 (familial partial lipodystrophy of the Dunnigan type)] is due to mutations in LMNA encoding the lamin A/C, belonging to the complex group of laminopathies that could comprise muscular and cardiac dystrophies, neuropathies and syndromes of premature aging. Some FPLDs are linked to loss-of-function mutations in the PPAR-gamma gene (peroxisome-proliferator-activated receptor gamma; FPLD3) with severe metabolic alterations but a less severe lipodystrophy compared with FPLD2. The metabolic syndrome, acquired, represents the most common form of lipodystrophy. HIV-infected patients often present lipodystrophies, mainly related to side effects of antiretroviral drugs together with insulin resistance and metabolic alterations. Such syndromes help to understand the mechanisms involved in insulin resistance resulting from altered fat repartition and could benefit from insulin-sensitizing effects of lifestyle modifications or of specific medications.

Adipose Tissue↗
PubMed2004

Patients with familial partial lipodystrophy of the Dunnigan type due to a LMNA R482W mutation show muscular and cardiac abnormalities.

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.

Adolescent↗
PubMed2003

A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy.

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.

Adult↗
PubMed2001

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Acanthosis Nigricans↗
PubMed2001

Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene.

Dunnigan-type familial partial lipodystrophy (FPLD), characterized by an abnormal body fat redistribution with insulin resistance, is caused by missense heterozygous mutations in A-type lamins (lamins A and C). A- and B-type lamins are ubiquitous intermediate filament proteins that polymerize at the inner face of the nuclear envelope. We have analyzed primary cultures of skin fibroblasts from three patients harboring R482Q or R482W mutations. These cells were euploid and able to cycle and divide. A subpopulation of these cells had abnormal blebbing nuclei with A-type lamins forming a peripheral meshwork, which was frequently disorganized. Inner nuclear membrane protein emerin, an A-type lamin-binding protein, strictly colocalized with this abnormal meshwork. Cells from lipodystrophic patients often had other nuclear envelope defects, mainly consisting of nuclear envelope herniations that were deficient in B-type lamins, nuclear pore complexes, lamina-associated protein 2 beta, and chromatin. The mechanical properties of nuclear envelopes were altered, as judged from the extensive deformations observed in nuclei from heat-shocked cells, and from the low stringency of extraction of their components. These structural nuclear alterations were caused by the lamins A/C mutations, as the same changes were introduced in human control fibroblasts by ectopic expression of R482W mutated lamin A.

Adult↗
PubMed2001

The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance.

Protease inhibitors used in the treatment of HIV infection have been causally associated with lipodystrophy and insulin resistance and were shown to alter adipocyte differentiation in cultured cells. We aimed to delineate the mechanism by which indinavir impaired adipocyte function. We report that indinavir altered neither the growth nor insulin sensitivity of 3T3-F442A preadipocytes, nor did it alter the initial step of their differentiation, i.e., clonal proliferation. However, adipose conversion was inhibited by indinavir (by 50-60%), as shown by 1) the decrease in the number of newly formed adipocytes; 2) the lower level of the adipogenic protein markers, sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and the insulin receptor (IR); and 3) the lack of SREBP-1 and PPAR-gamma immunoreactivity in the nucleus of most indinavir-treated cells. Partial adipose conversion also correlated with an accumulation of SREBP-1 at the nuclear periphery and an alteration in its electrophoretic mobility. Defective expression and nuclear localization of PPAR-gamma probably resulted from the decreased level of nuclear SREBP-1. Indinavir also rendered 3T3-F442A adipocytes resistant to insulin for mitogen-activated protein kinase activation at a step distal to IR substrate-1 tyrosine phosphorylation. Hence, indinavir impairs differentiation at an early step of adipose conversion probably involving the process controlling SREBP-1 intranuclear localization.

3T3 Cells↗
PubMed2001

[Major insulin resistance syndromes: clinical and physiopathological aspects].

Insulin resistance is a common metabolic disorder. It plays an important role in the metabolic syndrome (or syndrome X), type 2 diabetes, obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the insulin transduction pathways. Mutations of the insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of insulin resistance, as attested by the clinical characteristics of lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the familial partial lipodystrophy of the Dunnigan type, due to mutations of the lamin A/C gene, and the congenital generalized lipodystrophy, linked to alterations in the protein seipin. However, their physiopathology remains mysterious. Lamin A/C is indeed an ubiquitous nuclear protein, which is also mutated in a genetic squelettic and/or cardiac myopathy, and seipin is a protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular lipodystrophies which can be considered as caricatural models of the metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of insulin resistance.

Diabetes Mellitus, Type 2↗
PubMed2000

Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha.

In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon alpha (IFN-alpha) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 microg/kg/day x 5 days) given subcutaneously while continuing IFN-alpha therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 x 10(9)/l (6.9-108) white blood cells, 7.2 x 10(8)/kg (2.2-16.6) mononuclear cells, 39 x 10(4)/kg (4.8-403.5) CFU-GM and 4.2 x 10(6)/kg (0-58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-alpha therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-alpha therapy duration, although there was a significant impact from GM-CSF administration (P=0.01). After transplantation, 26 patients received IFN-alpha alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-alpha responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.

Adult↗
PubMed2000

A new missense mutation in the calcium-sensing receptor in familial benign hypercalcaemia associated with partial lipoatrophy and insulin resistant diabetes.

We studied two patients (a 54-year-old woman and her 16-year-old son) with familial benign hypocalciuric hypercalcaemia (FBHH) associated with severe insulin resistant diabetes in the context of a partial lipodystrophic syndrome. Sequencing of the entire coding sequence of the calcium-sensing receptor (CaR) gene revealed a novel heterozygous mutation at codon 395, leading to the substitution of a cysteine by an arginine residue (Cys395Arg) in the extracellular ligand-binding domain. This mutation was absent in two normocalcaemic relatives and in 54 control subjects. It was recently shown, in transfection studies, that the substitution of this amino acid results in incomplete receptor processing, a severe decrease in cell surface expression and altered signal transduction (Fan et al., 1998). This mutation is therefore likely to be responsible of the FBHH phenotype. A pathophysiological link between this mutation and insulin resistance remains unclear.

Adolescent↗
PubMed2000

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.

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.

Adipose Tissue↗
PubMed1999

Antiinsulin receptor autoantibodies induce insulin receptors to constitutively associate with insulin receptor substrate-1 and -2 and cause severe cell resistance to both insulin and insulin-like growth factor I.

We report here that antiinsulin receptor (anti-IR) autoantibodies (AIRs) from a newly diagnosed patient with type B syndrome of insulin resistance induced cellular resistance not only to insulin but also to insulin-like growth factor I (IGF-I) for the stimulation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase activities and of glycogen and DNA syntheses. The molecular mechanisms of this dual resistance were investigated. Patient AIRs bound the IR at the insulin-binding site and caused insulin resistance at the IR level by inducing a 50% decrease in cell surface IRs and a severe defect in the tyrosine kinase activity of the residual IRs, manifested by a loss of insulin-stimulated IR autophosphorylation and IR substrate-1 (IRS-1)/IRS-2 phosphorylation. In contrast, cell resistance to IGF-I occurred at a step distal to IGF-I receptors (IGF-IRs), as AIRs altered neither IGF-I binding nor IGF-I-induced IGF-IR autophosphorylation, but inhibited the ability of IGF-IRs to mediate tyrosine phosphorylation of IRS-1 and IRS-2 in response to IGF-I. Coimmunoprecipitation assays showed that in AIR-treated cells, IRs, but not IGF-IRs, were constitutively associated with IRS-1 and IRS-2, strongly suggesting that AIR-desensitized IRs impeded IGF-I action by sequestering IRS-1 and IRS-2. Accordingly, AIRs had no effect on the stimulation of mitogen-activated protein kinase activity or DNA synthesis by vanadyl sulfate, FCS, epidermal growth factor, or platelet-derived growth factor, all of which activate signaling pathways independent of IRS-1/IRS-2. Thus, AIRs induced cell resistance to both insulin and IGF-I through a novel mechanism involving a constitutive and stable association of IRS-1 and IRS-2 with the IR.

Aged↗