RAR-related orphan
receptor A isoform a (RORa1) A GPCR associated with severe obesity
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
Klar
J, et al. Eur J Hum Genet. 2005 Aug;13(8):928-34.