Skip to main content
SpringerLink
Log in

Fine-Mapping of Restless Legs Locus 4 (RLS4) Identifies a Haplotype over the SPATS2L and KCTD18 Genes

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Restless legs syndrome (RLS) is a sleep-related movement disorder that affects up to 15 % of the population. Linkage studies have identified several genomic loci in single families (12q, 14q, 9p, 2q, 20p and 16p, respectively). However, confirmation of these loci has not always been achieved, and causative mutations have not yet been identified. The locus on chromosome 2q33 (RLS4) was identified in two South Tyrolean families who shared a haplotype of microsatellite marker alleles across an 8.2-cM region. To pinpoint the gene localisation within RLS4, additional families from the same geographic region were evaluated, and linkage was replicated in one family. Within the candidate region, we initially found a haplotype of 23 single nucleotide polymorphism markers spanning 131.6 Kb shared by all affected members of the three linked families. Using a next generation sequencing approach, we further restricted the shared candidate region to 46.9 Kb over the potassium channel-related gene KCTD18 and exons 10-13 of SPATS2L.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  • Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  PubMed  CAS  Google Scholar 

  • Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J (2003) Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 4:101–119

    Article  PubMed  Google Scholar 

  • Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G (2003) Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 126:1485–1492

    Article  PubMed  Google Scholar 

  • Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q (2004) Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 74:876–885

    Article  PubMed  CAS  Google Scholar 

  • Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Rouleau GA (2001) Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet 69:1266–1270

    Article  PubMed  CAS  Google Scholar 

  • Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363

    PubMed  CAS  Google Scholar 

  • Levchenko A, Provost S, Montplaisir JY, Xiong L, St-Onge J, Thibodeau P, Riviere JB, Desautels A, Turecki G, Dube MP, Rouleau GA (2006) A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology 67:900–901

    Article  PubMed  CAS  Google Scholar 

  • Levchenko A, Montplaisir JY, Asselin G, Provost S, Girard SL, Xiong L, Lemyre E, St-Onge J, Thibodeau P, Desautels A, Turecki G, Gaspar C, Dube MP, Rouleau GA (2009) Autosomal-dominant locus for restless legs syndrome in French-Canadians on chromosome 16p121. Mov Disord 24:40–50

    Article  PubMed  Google Scholar 

  • Ohayon MM, O'Hara R, Vitiello MV (2012) Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev 16:283–295

    Article  PubMed  Google Scholar 

  • Pattaro C, Marroni F, Riegler A, Mascalzoni D, Pichler I, Volpato CB, Dal Cero U, De Grandi A, Egger C, Eisendle A, Fuchsberger C, Gogele M, Pedrotti S, Pinggera GK, Stefanov SA, Vogl FD, Wiedermann CJ, Meitinger T, Pramstaller PP (2007) The genetic study of three population microisolates in south tyrol (MICROS): study design and epidemiological perspectives. BMC Med Genet 8:29

    Article  PubMed  Google Scholar 

  • Pichler I, Marroni F, Volpato CB, Gusella JF, Klein C, Casari G, De Grandi A, Pramstaller PP (2006) Linkage analysis identifies a novel locus for restless legs syndrome on chromosome 2q in a South Tyrolean population isolate. Am J Hum Genet 79:716–723

    Article  PubMed  CAS  Google Scholar 

  • Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, Ripke S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Hogl B, Frauscher B, Gschliesser V, Poewe W, Peglau I, Vodicka P, Vavrova J, Sonka K, Nevsimalova S, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Muller-Myhsok B, Meitinger T, Winkelmann J (2008) PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 40:946–948

    Article  PubMed  CAS  Google Scholar 

  • Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, Palsson S, Sigmundsson T, Sigurdsson AP, Eiriksdottir I, Soebech E, Bliwise D, Beck JM, Rosen A, Waddy S, Trotti LM, Iranzo A, Thambisetty M, Hardarson GA, Kristjansson K, Gudmundsson LJ, Thorsteinsdottir U, Kong A, Gulcher JR, Gudbjartsson D, Stefansson K (2007) A genetic risk factor for periodic limb movements in sleep. N Engl J Med 357:639–647

    Article  PubMed  CAS  Google Scholar 

  • Vogl FD, Pichler I, Adel S, Pinggera GK, Bracco S, De Grandi A, Volpato CB, Aridon P, Mayer T, Meitinger T, Klein C, Casari G, Pramstaller PP (2006) Restless legs syndrome: epidemiological and clinicogenetic study in a South Tyrolean population isolate. Mov Disord 21:1189–1195

    Article  PubMed  Google Scholar 

  • Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, Fulda S, Putz B, Eckstein G, Hauk S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Peglau I, Eisensehr I, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Muller-Myhsok B, Meitinger T (2007) Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 39:1000–1006

    Article  PubMed  CAS  Google Scholar 

  • Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, Trenkwalder C, Dauvilliers Y, Polo O, Hogl B, Berger K, Fuhs A, Gross N, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Xiong L, Montplaisir J, Rouleau GA, Fietze I, Vavrova J, Kemlink D, Sonka K, Nevsimalova S, Lin SC, Wszolek Z, Vilarino-Guell C, Farrer MJ, Gschliesser V, Frauscher B, Falkenstetter T, Poewe W, Allen RP, Earley CJ, Ondo WG, Le WD, Spieler D, Kaffe M, Zimprich A, Kettunen J, Perola M, Silander K, Cournu-Rebeix I, Francavilla M, Fontenille C, Fontaine B, Vodicka P, Prokisch H, Lichtner P, Peppard P, Faraco J, Mignot E, Gieger C, Illig T, Wichmann HE, Muller-Myhsok B, Meitinger T (2011) Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q121. PLoS Genet 7:e1002171

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the study participants and the primary care physicians of the villages for their participation and collaboration in this research project. We thank Martin Gögele and Daniel Taliun for their technical support. The study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation.

Author information

Authors and Affiliations

  1. Center for Biomedicine, European Academy Bozen/Bolzano (EURAC) (Affiliated institute of the University of Lübeck), Drususallee 1, 39100, Bozen/Bolzano, Italy

    Irene Pichler, Christine Schwienbacher, Alessandra Zanon, Alice Serafin, Maurizio F. Facheris, Cristian Pattaro, Andrew A. Hicks & Peter P. Pramstaller

  2. Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy

    Christine Schwienbacher

  3. Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA

    Christian Fuchsberger

  4. Institute of Applied Genomics, Udine, Italy

    Fabio Marroni

  5. Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    Yiping Shen & James F. Gusella

  6. Department of Laboratory Medicine, Children’s Hospital Boston, Boston, MA, USA

    Yiping Shen

  7. Department of Pathology, Harvard Medical School, Boston, MA, USA

    Yiping Shen

  8. Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yiping Shen

  9. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SciLifeLab Uppsala, Uppsala University, Uppsala, Sweden

    Christian Tellgren-Roth & Ulf Gyllensten

  10. Department of Genetics, Harvard Medical School, Boston, MA, USA

    James F. Gusella

  11. Department of Neurology, General Central Hospital, Bolzano, Italy

    Peter P. Pramstaller

  12. Department of Neurology, University of Lübeck, Lübeck, Germany

    Peter P. Pramstaller

Authors
  1. Irene Pichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine Schwienbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Zanon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Fuchsberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alice Serafin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maurizio F. Facheris
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fabio Marroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cristian Pattaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yiping Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christian Tellgren-Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ulf Gyllensten
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. James F. Gusella
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andrew A. Hicks
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Peter P. Pramstaller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter P. Pramstaller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pichler, I., Schwienbacher, C., Zanon, A. et al. Fine-Mapping of Restless Legs Locus 4 (RLS4) Identifies a Haplotype over the SPATS2L and KCTD18 Genes. J Mol Neurosci 49, 600–605 (2013). https://doi.org/10.1007/s12031-012-9891-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-012-9891-5

Keywords

Search

Navigation