Phenotypic Gender Differences in Subjects With Familial Partial Lipodystrophy (Dunnigan Variety) Due to a Nuclear Lamin A/C R482W Mutation

Araújo‐Vilar, David; Loidi, Lourdes; Domínguez, F. Higuera; Cabezas-Cerrato, J

doi:10.1055/s-2003-38388

Cited by 48 publications

(44 citation statements)

References 17 publications

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“…1E). Similar values for truncal and peripheral skinfolds were observed in the proband and in normal women, unlike those of typical FPLD R482W LMNAmutated women or atypical lipodystrophic women bearing the R582H LMNA mutation (13,14) (Fig. 2A).…”

Section: Case Reportsupporting

confidence: 75%

Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation

et al. 2005

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Particular forms of polycystic ovary syndrome with severe hyperandrogenism, acanthosis nigricans, and marked insulin resistance, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations. However, the majority of affected individuals do not have such mutation, arguing for the genetic heterogeneity of this syndrome. The familial partial lipodystrophy of the Dunnigan type, one of the diseases due to mutations in the lamin A/C (LMNA) gene, is characterized by a lipodystrophic phenotype and shares some clinical and metabolic features with the type A syndrome. We describe here the case of a nonobese 24-year-old woman affected with type A syndrome without clinical lipodystrophy. We linked this phenotype to a novel heterozygous missense mutation in the LMNA, predicting a G602S amino acid substitution in lamin A. This mutation cosegregated with impaired glucose tolerance, insulin resistance, and acanthosis nigricans in the absence of clinical lipodystrophy in the family. The skin fibroblasts from the proband exhibited nuclear alterations similar to those described in other laminopathies, and showed several defects in the insulin transduction pathway. This study further extends the vast range of diseases linked to LMNA mutations and identifies another genetic cause for the type A insulin resistance syndrome. Diabetes 54:1873-1878, 2005 P olycystic ovary syndrome (PCOS) is the most common endocrine abnormality in women of reproductive age and the main cause of anovulatory infertility (1). It is associated with hyperandrogenemia, metabolic alterations including insulin resistance, and an increased risk of type 2 diabetes and cardiovascular disease. The primary cause of PCOS remains elusive, although there is evidence that genetic factors have an important role (2). Particular forms of PCOS with acanthosis nigricans, severe insulin resistance, and hyperandrogenism, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations (3). However, many affected individuals do not have such a mutation, which lends support to the genetic heterogeneity of this syndrome (4).Lamins are the main components of the nuclear lamina, a filamentous network located between inner nuclear membrane and chromatin that plays a fundamental role in nuclear organization in all differentiated cells (5). Mutations in lamins A and C, which are alternatively spliced products of the lamin A/C (LMNA) gene, are responsible for several genetic diseases, including familial partial lipodystrophy of the Dunnigan type (FPLD) (5). Women with FPLD often have irregular menses and hyperandrogenemia, as well as severe insulin resistance, dyslipidemia, and atherosclerotic vascular disease (6 -8). These common clinical and metabolic features of FPLD and type A insulin resistance syndrome led us to search for mutations of the LMNA gene in a patient with a typical type A phenotype.We describe the case of a nonobese 24-year-old woman with severe hyperandrogenemia who had clinical, hormonal, and morphological ov...

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Section: Case Reportsupporting

confidence: 75%

Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation

et al. 2005

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“…The most prominent difference between humans with FPLD2 and our FPLD mice relates to gender. Metabolic complications such as diabetes, hyperlipidemia, and cardiovascular disease occur more often in women than in men (35,47). We found the FPLD2 phenotype to be more prominent in male mice than in female mice.…”

Section: Discussionmentioning

confidence: 61%

“…Patients affected with FPLD2 present with metabolic complications such as glucose intolerance, insulin resistance, and fatty liver (35)(36)(37). These parameters were examined in our FPLD transgenic mouse.…”

Section: Fpld Mice Have Decreased Insulin Sensitivity and Fatty Livermentioning

confidence: 99%

The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation

Wojtanik

Edgemon

Viswanadha

et al. 2009

Journal of Lipid Research

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We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance.-Wojtanik, K. M., K. Edgemon, S. Viswanadha, B. Lindsey, M. Haluzik, W. Chen, G. Poy, M. Reitman, and C. Londos. The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation.

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“…Postpubertal onset of sc lipoatrophy affecting the four limbs and abdomen but sparing face and neck, calves hypertrophy, hypertriglyceridemia, and insulin resistance, more severe in women than in men (13,32,33), are typical features present in most cases.…”

Section: Discussionmentioning

confidence: 99%

New Metabolic Phenotypes in Laminopathies:LMNAMutations in Patients with Severe Metabolic Syndrome

Decaudain

Vantyghem

Guerci

et al. 2007

The Journal of Clinical Endocrinology &Amp; Metabolism

139

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We describe here new phenotypes of metabolic laminopathy associated with non-codon 482 LMNA mutations and characterized, in the absence of obvious clinical lipoatrophy, by severe metabolic alterations and frequent muscle signs (muscular hypertrophy, myalgias, or weakness). Dual-energy x-ray absorptiometry and/or cross-sectional abdominal and thigh imaging can help diagnosis by revealing subclinical lipodystrophy. The prevalence and pathophysiology of metabolic laminopathies need to be studied further.

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Phenotypic Gender Differences in Subjects With Familial Partial Lipodystrophy (Dunnigan Variety) Due to a Nuclear Lamin A/C R482W Mutation

Cited by 48 publications

References 17 publications

Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation

Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation

The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation

New Metabolic Phenotypes in Laminopathies:LMNAMutations in Patients with Severe Metabolic Syndrome

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