A mutation in the c-Fos gene associated with congenital generalized lipodystrophy

Abstract

BackgroundCongenital generalized lipodystrophy (CGL) or Berardinelli–Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes.Methods and resultsIn a patient with CGL and insulin resistance we 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. Sequence analyses revealed a novel homozygous point mutation (c.–439, T→A) in the patients’ c-fos promoter. The point mutation was located upstream of the well characterized promoter elements in a region with no homology to any known cis-elements. The identified mutation was not detected in a total of n=319 non lipodystrophic probands. In vitro analyses revealed that the mutation facilitates the formation of a novel and specific protein/DNA complex. Using mass spectrometry we identified the proteins of this novel complex. Cellular investigations demonstrate that the wild type c-fos promoter can reconstitute the signaling defect in the patient, excluding further upstream signaling alterations, and vice versa the investigations with the c-fos promoter containing the identified mutation generally reduce basal and inducible c-fos transcription activity. As a consequence of the identified point mutation gene expression including c-Fos targeted genes is significantly altered, shown exemplified in cells of the patient.ConclusionThe immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. According to the role of c-fos in adipocyte differentiation our findings of a mutation that initiates a repression mechanism at c-fos promoter features the hypothesis that diminished c-fos expression might play a role in CGL by interfering with adipocyte development.

Congenital generalized lipodystrophies—new insights into metabolic dysfunction

“…Furthermore, four molecularly distinct subtypes have been described and two other closely related phenotypes due to additional loci have been reported. [35][36][37][38][39][40] In view of these developments, we recommend updated diagnostic criteria for CGL (out lined in Box 2). In addition, patients with CGL might have prominent superficial subcutaneous veins due to lack of fat.…”

“…38,[73][74][75][76] In addition, phenotypes that are closely related to CGL have been reported that are associ ated with biallelic mutations in the gene that encodes peroxisome proliferator activated receptor γ (PPARG) 39 and a protooncogene cFOS protein (FOS). 40,77 Type 1 CGL Type 1 CGL, (Online Mendelian Inheritance in Man [OMIM] #608594), 78 is caused by mutations in AGPAT2. AGPAT2 is located on chromosome 9q34 and encodes lysophosphatidic acid acyltransferaseβ, which is involved in triglyceride (triacylglycerol) biosyn thesis.…”

Congenital Lipodystrophies and Dyslipidemias

“…In a few cases, other BSCL-causative genes have been identified: CAV1 (BSCL3) encoding caveolin 1 has been reported in single patient [12] and PTRF (BSCL4) encoding polymerase I and transcript release factor also known as cavin 1 [13,14] has been reported in about 20 patients. Recently, a mutation in the FOS (encoding the transcription factor c-Fos) promoter has been identified in a single patient, in whom the phenotype and the mode of inheritance are not well characterized [15]. It is likely that additional loci exist, as some patients with BSCL do not harbor mutations in any of the known genes.…”

“…Plasma levels of phospholipids and total cholesterol are usually within the normal range or are slightly elevated, whereas high-density lipoprotein (HDL) levels are decreased. However, increased plasma total cholesterol levels have sometimes been reported [12,15]. Free fatty acids (FFA) levels are variable, normal, or slightly elevated.…”

Clinical Utility Gene Card for: Congenital Generalized Lipodystrophy

“…A de novo variant in the promoter of the FOS gene has also been reported in a generalized lipodystrophy, though this disease has not entered the CGL classification so far. 1 The description of all these rare entities is beyond the scope of this clinical utility gene card, which will focus on the so-called CGL.…”