Parkin gene modifies the effect of RLS4 on the age at onset of restless legs syndrome (RLS)

A co-occurrence of restless legs syndrome (RLS) and Parkin mutations has been described. In South Tyrolean RLS patients, a novel RLS locus has been found (RLS4) and recurrent Parkin mutations have been reported. By a systematic screen we investigated the presence of founder Parkin mutations in South Tyrolean RLS patients with known carrier status at the RLS4 locus and assessed whether these mutations alone or in combination influence the RLS phenotype measured by three quantitative RLS traits (age at onset (AAO) and two severity measurements). The Parkin mutation alone showed no effect, whereas RLS4 had a significant effect on the AAO (P=0.0096, decrease of AAO of 9.1 years), but did not influence severity. Carriers of both, a Parkin mutation and the RLS4 haplotype, showed an association with AAO (P=0.0016), corresponding to an anticipation of RLS onset age of 16.9 years. However, there was no effect on the disease severity. Our results suggest that the occurrence of a heterozygous Parkin mutation works in tandem with the gene at the RLS4 locus to lower the AAO in RLS.