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

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.