GTC On Line News No.413

******** GTC On Line News No.413*******
　　　　　　２００３年　７月２４日
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　GTC On Line News No.410（２００３年　７月２３日）でお知らせした代謝内科学セミナーの案内文に文字化けしている箇所がありました。メールに添付されていた Word文書をコピーペーストした際に文字化けしたのですが気づきませんでした。申し訳ありませんでした。お詫びして訂正します。

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演　者：Jocelyne Magre Ph.D.
Research tenure position (Senior Investigator),
INSERM U.402, Saint-Antoine Faculty of Medicine, Paris, France.
演　題："Genetic of Lipodystrophies"
日　時：２００３年８月１２日（火）、１８：００～１９：００
場　所：山崎記念館２階　第1研修室
［要　旨］
　Lipodystrophies include several syndromes characterized by alterations in body fat distribution and insulin resistance. These also display the clinical features of acanthosis nigricans, muscular hypertrophy, hyperandrogenism, hepatomegaly and, at the biological level, altered glucose tolerance or diabetes and hypertriglyceridemia. These syndromes are classified according to the pattern of lipoatrophy being either generalized or localized.
In the generalized lipodystrophies, both sub-cutaneous and visceral adipose tissues are near absent. Two phenotypes are distinguished according to the age at onset of lipoatrophy: the congenital form or Berardinelli-Seip congenital lipodystrophy (BSCL) with absence of adipose tissue from birth or occurring in early infancy and the delayed form or Lawrence syndrome where lipoatrophy occurs at a later age. BSCL is a heterogeneous genetic disease transmitted as an autosomal recessive trait with, until now, two genes identified. The first gene, BSCL2, that we identified, encodes the protein "seipin" of unknown function and without similarities with known proteins. The second disease-causing gene, AGPAT2, encodes the enzyme 1-acyl-glycerol-3-phosphate acyltransferase-beta. This enzyme catalyses the acylation of lysophosphatidic acid to form phosphatidic acid and is therefore involved in the synthesis of triglycerides and glycerophospholipids. The large majority of BSCL patients disclose mutations in either the seipin gene or AGPAT2; suggesting that these are the two major genes involved in the etiology of BSCL. Patients harboring mutations in the seipin gene appears to present somewhat a more severe phenotype with a higher prevalence of intellectual impairment, cardiomyopathy and an increased risk of premature death. The genetic basis of Lawrence syndrome is still a matter of debate. No disease-causing genes have been yet identified and other factors such as immune mechanisms are likely to be involved in its etiology.
Partial lipodystrophies regroups disorders with a selective loss of adipose tissue from various regions of the body. Among the genetic types, the familial partial lypodystrophy of the Dunnigan-type (FPLD) is characterized by loss at puberty of adipose tissue in the limbs, buttocks and trunk with fat accumulation in the neck and face. It is inherited as a dominant trait, and is caused in most cases by heterozygous mutations of LMNA. This gene encodes the type-A lamins that are ubiquitous structural proteins that polymerize to form the nuclear lamina network. Because other diseases are also due to alterations in LMNA, the mechanisms underlying the FPLD phenotype is not yet understood. However, one hypothesis is that mutations, which are located in the carboxyl-terminal end of the lamin from most of FPLD patients, might alter the interactions with DNA and the adipogenic transcription factor SREBP-1 (Sterol Regulatory Element Binding Protein 1). Finally, there is emerging evidence that some rare patients with partial lipodystrophies with features of X-syndrome disclose heterozygous mutations in the peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor that plays an important role in adipocyte differentiation. So far, these mutations are located in the ligand binding domain and have been shown, in some cases, to impair the transcriptional activity of PPARg.
In conclusion, lipodystrophies regroups disorders with diverse etiologies. The genetic diagnoses progressively enlighten the various phenotypes. The characterization of the mechanisms by which alterations in the genes cause those phenotypes is likely to provide significant insights into the molecular basis of lipodystrophy.

多数の御来聴を歓迎します。
連絡先：医学薬学研究部代謝内科学　荒木　栄一（内線5169）