******** GTC On Line News No.410*******
2003年 7月23日
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医学薬学研究部代謝内科学分野から、下記セミナーの案内がありましたのでお知ら
せします。
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演 者:Jocelyne Magr 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 メseipinモ of unknown function and without similarities with known
proteins. The second disease-causing gene, AGPAT2, encodes the enzyme
1-acyl-glycerol-3-phosphate acyltransferase-ァ. 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-_ (PPAR-_), 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 PPAR_.
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)
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