Congenital generalized lipodystrophy linked to a mutation in the c-Fos gene


Lipodystrophy can be acquired or inherited and results in partially or complete loss of adipose tissue. In the most severe form, congenital generalized lipodystrophy ( CGL ) or Berardinelli–Seip congenital lipodystrophy ( BSCL ), total absence of adipose tissue is associated with altered development, fatty liver, muscular hypertrophy, hypertriglyceridemia, acanthosis nigricans, hyperinsulinism and type-2-diabetes.

Congenital generalized lipodystrophy is rare with estimated 1:10 million births and thought to be a genetic syndrome with autosomal recessive trait. In humans several candidate genes ( BSCL1-4 ) were found to be associated to the syndrome. BSCL1/AGPAT2 and BSCL2/seipin are identified in the majority of CGL patients. In single families BSCL3/caveolin-1 and BSCL4/PTRF-Cavin were identified.
The BSCL genes are part of mechanisms involved in the adipocyte formation and growth including lipid droplet formation vesicle transport or and glycerophospholipid synthesis. Thus CGL have been valuable models for the identification of new genetic loci involved in development, distribution and plasticity of white fat cells. Although patients are rare and an estimated 1 of 4 existing cases has been included into studies, not all individuals identified bare mutations in these target genes.

Lipodystrophy resemble syndromes of disturbed adipocyte biology or metabolism but the severe congenital forms are thought to be related to malfunctions in adipocyte development.
Therefore genes involved in the differentiation of adipocytes, especially transcription factors, are hot candidates. Prominent examples are PPAR-gamma, SREBP-1c in HIV therapy and SREBP-1c or C/EBP in mouse models causing lipodystrophy.
Another potential candidate is the transcription factor c-Fos a member of the AP-1 complex that is essential to initiate adipocyte differentiation. Accompanied with peak c-fos gene expression a sequential gene expression cascade of specific transcription factors necessary in adipocyte development is temporarily initiated leading to fully differentiated adipocytes. C-fos has been proven to be essential in this transcriptional activation and knockdown of c-fos abolished the ongoing differentiation process.

In a patient with CGL and insulin resistance, researchers investigated the known candidate genes but the patient did not carry a relevant mutation. Analyses of the insulin activated signal transduction pathways in isolated fibroblasts of the patient revealed a postreceptor defect altering expression of the immediate early gene c-fos.

According to investigators a diminished c-fos expression might play a role in CGL by interfering with adipocyte development. ( Xagena )

Knebel B et al, Orphanet Journal of Rare Diseases 2013, 8:119

XagenaMedicine_2013



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