RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

Abstract

We have identified a family comprising a mother and two children with idiopathic and profound obesity body mass index (BMI) 41 -49 kg/m 2 . The three family members carry a balanced reciprocal chromosome translocation t(4;15). We present here the clinical features of the affected individuals as well as the physical mapping and cloning of the chromosomal breakpoints. A detailed characterisation of the chromosomal breakpoints at chromosomes 4 and 15 revealed that the translocation is almost perfectly balanced with a very short insertion/deletion. The chromosome 15 breakpoint is positioned in intron 1 of the RAR-related orphan receptor A isoform 1 (RORa1) and the chromosome 4 breakpoint is positioned 133 kb telomeric to the transcriptional start of the unc-5 homolog B (UNC5C) and 154 kb centromeric of the transcriptional start of the pyruvate dehydrogenase (lipoamide) alpha 2 (PDHA2). The rearrangement creates a fusion gene, which includes the RORa1 exon 1 and UNC5C that is expressed in frame in adipocytes from the affected patients. We also show that this transcript is translated into a protein. From previous reports, it is shown that RORa1 is implicated in the regulation of adipogenesis and lipoprotein metabolism. We hypothesise that the obesity in this family is caused by (i) haploinsufficiency for RORa1 or, (ii) a gain of function mechanism mediated by the RORa1 -UNC5C fusion gene.

Systematic Analysis of Circadian Genes in a Population-Based Sample Reveals Association of TIMELESS with Depression and Sleep Disturbance

“…Consequently, one might hypothesize that altered levels or function of ARNTL may contribute to hypertension and type 2 diabetes via mechanisms related to disturbed sleep and mood. In addition, we obtained evidence for association of the promoter and intron 1 region of RORA with depression and sleep disturbances, and this same region has been earlier associated with severe obesity [69]. Thus, these findings may offer one possible molecular mechanism for the association between metabolic syndrome and depressive disorders in general population [70], [71].…”

Circadian gene variants in cancer

“…The deregulation and/or SNPs of Rorα and/or γ in humans have been linked to an increased risk of breast and prostate cancers, colorectal adenocarcinomas, pituitary and thyroid tumors (122, 255–260), immune deficiency (261), obesity, insulin resistance, and adipogenesis (262–264). The cancer risk of mice lacking Rorα or γ ( Rorα −/− or Rorγ −/− ) has not been carefully studied.…”

Retinoic acid-related orphan receptors α and γ: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity

“…In humans, two studies have revealed a connection between RORα, obesity, and type 2 diabetes. A rearrangement resulting in disruption of human RORα1 was found to be associated with severe obesity (Klar et al, 2005), while a recent GWAS study showed an association between a single nucleotide polymorphism in RORα (rs7164773) and increased risk for type 2 diabetes in the Mexico Mestizo population (Gamboa-Melendez et al, 2012). …”