Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a 
sensory-motor neurological disorder with a circadian component. RLS is 
characterized by uncomfortable sensations in the extremities, generally at night 
or during sleep, which often leads to an uncontrollable urge to move them for 
relief. Recently, genomic studies identified single-nucleotide polymorphisms in 
BTBD9, along with three other genes, as being associated with a higher risk of 
RLS. Little is known about the function of BTBD9 or its potential role in the 
pathophysiology of RLS. We therefore examined a line of Btbd9 mutant mice we 
recently generated for phenotypes similar to symptoms found in RLS patients. We 
observed that the Btbd9 mutant mice had motor restlessness, sensory alterations 
likely limited to the rest phase, and decreased sleep and increased wake times 
during the rest phase. Additionally, the Btbd9 mutant mice had altered serum 
iron levels and monoamine neurotransmitter systems. Furthermore, the sensory 
alterations in the Btbd9 mutant mice were relieved using ropinirole, a 
dopaminergic agonist widely used for RLS treatment. These results, taken 
together, suggest that the Btbd9 mutant mice model several characteristics 
similar to RLS and would therefore be the first genotypic mouse model of RLS. 
Furthermore, our data provide further evidence that BTBD9 is involved in RLS, 
and future studies of the Btbd9 mutant mice will help shine light on its role in 
the pathophysiology of RLS. Finally, our data argue for the utility of Btbd9 
mutant mice to discover and screen novel therapeutics for RLS.