Role of MEIS1 in restless legs syndrome: From GWAS to functional studies in mice

MEIS1 is a transcription factor playing an important role in the development of several organs, including central and peripheral nervous systems. A genetic locus spanning the MEIS1 coding region has been associated with the risk of RLS in genome-wide association studies, with increasing evidence that MEIS1 is the causal RLS gene. The RLS-linked genetic signal has been mapped to an intronic regulatory element within MEIS1. This element plays a role in the ganglionic eminences of the developing forebrain, with the RLS risk allele related to a reduced activation of the enhancer. This suggests that the ganglionic eminences play an important role in the development of genetic susceptibility to RLS. In addition, rare variants within MEIS1 have been shown to contribute to the disease risk. These variants were identified first in RLS families and later found in further RLS cases by targeted sequencing. Some of these variants alone are sufficient to suppress MEIS1 function in neural development, providing further evidence of the importance of neurodevelopmental processes in the pathological mechanism of MEIS1 in RLS. Heterozygous Meis1 inactivation in mice causes hyperactivity at the onset of the inactive period, consistent with human RLS. In addition, these mice revealed an effect of MEIS1 on the dopaminergic system at both the spinal and supraspinal level. More studies are needed in human genetics to determine the exact role of MEIS1 variants in the risk of RLS, as well as in functional genetics and animal studies to further elucidate the pathological mechanism of MEIS1 in RLS.