Cytogenetic location: 9p24-p22 Genomic coordinates (GRCh38): 9:1-19,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p24-p22 | {Restless legs syndrome 3} | 610438 | 2 |
Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003).
For additional information and a discussion of genetic heterogeneity of restless legs syndrome, see RLS1 (102300).
Chen et al. (2004) characterized 15 large and extended multiplex pedigrees consisting of 453 subjects, of whom 134 were affected with restless legs syndrome. A weighted average correlation of 0.17 between first-degree relatives was obtained, and heritability was estimated to be 0.60 for all types of relative pairs, indicating that the disorder was highly heritable in this cohort. Model-free linkage analysis identified 1 novel significant RLS susceptibility locus on 9p24-p22 with a multipoint nonparametric linkage (NPL) score of 3.22. Suggestive evidence of linkage indicated by NPL scores between 2 and 3 were found on chromosomes 3, 4, 5, and 6. Model-based linkage analysis, with the assumption of an autosomal dominant mode of inheritance, validated the linkage of RLS to 9p24-p22 in 2 families (2-point lod score of 3.77; multipoint lod score of 3.91). A marker between D12S1044 and D12S78 on chromosome 12q22-q23, and 2.4 cM from D12S78, yielded an NPL score of 1.29, which Chen et al. (2004) suggested might provide indirect confirmation of an RLS locus (RLS1; 102300) on chromosome 12q22-q23.
Ray and Weeks (2005) concluded, contrary to the findings of Chen et al. (2004), that there is no convincing evidence of linkage for RLS on 9p. In a rebuttal, Chen et al. (2005) defended their analysis as methodologically sound and pointed out that by personal communication they had information on the finding of a 9p24-p22 RLS locus in a large family in Germany studied by another research group.
Liebetanz et al. (2006) reported a large Bavarian family in which 16 individuals had RLS, including 9 with onset before age 32 years and 7 with onset after age 32 years. Transmission disequilibrium tests indicated linkage to D9S1810. Genomewide linkage analysis followed by fine mapping yielded maximum 2-point and multipoint lod scores of 3.88 and 3.78, respectively, at D9S285. The 1-unit lod interval delineated an 11.1-cM region between D9S256 and D9S157. These results were obtained when considering only early-onset patients and unaffected family members. When all affected individuals, regardless of age at onset, were included in the linkage analysis, lod scores were solidly negative for the entire region on chromosome 9p; the authors postulated intrafamilial heterogeneity.
Schormair et al. (2008) identified association of RLS with PTPRD (601598) at 9p24-p23 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czech Republic, and Canada. Two independent SNPs in the 5-prime UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda-corrected) = 5.91 x 10(-10), odds ratio = 1.44; and rs1975197, P(nominal/lambda-corrected) = 5.81 x 10(-9), odds ratio = 1.31). These 2 association signals are 0.41 Mb apart and map to introns 8 and 10 of PTPRD, within 2 separate linkage disequilibrium blocks. Sequence analysis revealed no mutations in 35 coding and 10 noncoding exons of PTPRD among 9 affected individuals from an RLS3-linked family, 3 index cases from families with RLS in which linkage to RLS3 was not excluded, and 1 control compared to the reference sequence. The familial relative risk figures estimated by the risk to sibs of an affected individual (lambda-S) were all below 1.04 and explain only a minor portion of the original RLS3 linkage signal. The RLS-associated SNPs are common and showed weak effects (rs4626664, odds ratio = 1.44, 95% confidence interval = 1.3 to 1.6; rs1975197, odds ratio = 1.31, 95% confidence interval = 1.2 to 1.4). Schormair et al. (2008) failed to detect rare alleles with strong effects within this gene that could explain the linkage signal. The association of 2 independent signals strengthened the evidence for PTPRD as a gene influencing risk of RLS.
Lohmann-Hedrich et al. (2008) reported a German family with RLS spanning 4 generations in an autosomal dominant pattern of inheritance. Disease onset was mainly in childhood or adolescence. Linkage analysis identified a locus on chromosome 9p (maximum lod score of 3.60 at all markers between D9S976 and D9S2183) that was separated from RLS3 by approximately 5 cM (2.3 Mb). Lohmann-Hedrich et al. (2008) termed this locus RLS3* to distinguish it from RLS3. Twelve patients shared a haplotype flanked by D9S974 and D9S1118 in a 9.9-Mb region that was centromeric to RLS3. However, 11 patients shared a larger haplotype extending telomeric to D9S2189 that overlapped with the RLS3 locus. Several affected individuals had a cooccurrence of psychiatric disorders.
Chen et al. (2004) found no mutations in 3 genes from the 9p24-p22 region that were considered to be strong RLS candidates on the basis of their location and physiology: MPDZ (603785), SLC1A1 (133550), and KCNV2 (607604).
Bonati, M. T., Ferini-Strambi, L., Aridon, P., Oldani, A., Zucconi, M., Casari, G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 126: 1485-1492, 2003. [PubMed: 12764067] [Full Text: https://doi.org/10.1093/brain/awg137]
Chen, S., Li, L., Rao, S., Ondo, W. G., Wang, Q. Reply to Ray and Weeks: linkage for restless legs syndrome on chromosome 9p is significant. (Letter) Am. J. Hum. Genet. 76: 707-710, 2005.
Chen, S., Ondo, W. G., Rao, S., Li, L., Chen, Q., Wang, Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am. J. Hum. Genet. 74: 876-885, 2004. [PubMed: 15077200] [Full Text: https://doi.org/10.1086/420772]
Liebetanz, K. M., Winkelmann, J., Trenkwalder, C., Putz, B., Dichgans, M., Gasser, T., Muller-Myhsok, B. RLS3: fine-mapping of an autosomal dominant locus in a family with intrafamilial heterogeneity. Neurology 67: 320-321, 2006. [PubMed: 16864828] [Full Text: https://doi.org/10.1212/01.wnl.0000224886.65213.b5]
Lohmann-Hedrich, K., Neumann, A., Kleensang, A., Lohnau, T., Muhle, H., Djarmati, A., Konig, I. R., Pramstaller, P. P., Schwinger, E., Kramer, P. L., Ziegler, A., Stephani, U., Klein, C. Evidence for linkage of restless legs syndrome to chromosome 9p: are there two distinct loci? Neurology 70: 686-694, 2008. [PubMed: 18032746] [Full Text: https://doi.org/10.1212/01.wnl.0000282760.07650.ba]
Ray, A., Weeks, D. E. No convincing evidence of linkage for restless legs syndrome on chromosome 9p. (Letter) Am. J. Hum. Genet. 76: 705-707, 2005. [PubMed: 15747259] [Full Text: https://doi.org/10.1086/429392]
Schormair, B., Kemlink, D., Roeske, D., Eckstein, G., Xiong, L., Lichtner, P., Ripke, S., Trenkwalder, C., Zimprich, A., Stiasny-Kolster, K., Oertel, W., Bachmann, C. G., and 20 others. PTPRD (protein tyrosine phosphate receptor type delta) is associated with restless leg syndrome. Nature Genet. 40: 946-948, 2008. [PubMed: 18660810] [Full Text: https://doi.org/10.1038/ng.190]