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Evidence for linkage of restless legs syndrome to chromosome 9p

Are there two distinct loci?

From the Department of Neurology (K.L.-H., A.N., T.L., A.D., C.K.), Institute of Medical Biometry and Statistics (A.K., I.R.K., A.Z.), and Department of Human Genetics (E.S.), University at Lübeck, Lübeck, Germany; Department of Neuropediatrics, University of Kiel, Kiel, Germany (A.N., H.M., U.S.); Institute of Genetic Medicine, EURAC Research, Bolzano, Italy (P.P.P.); and Department of Neurology, Oregon Health and Sciences University, Portland, OR (P.L.K.).

Address correspondence and reprint requests to Dr. Christine Klein, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany christine.klein{at}neuro.uni-luebeck.de

Background: Restless legs syndrome (RLS) is a common sensory-motor disorder characterized by paresthesias and an intense urge to move the legs with a considerable familial aggregation. To date, no gene mutation has been found, but five gene loci have been mapped in primary RLS to chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1 through 5).

Patients/Methods: We identified a four-generational German RLS family with 37 family members including 15 affected cases. We performed linkage analysis using microsatellite markers at the five known loci. Prompted by the identification of a potentially shared haplotype near the RLS3 locus, we expanded the investigated linkage region on chromosome 9p using additional DNA markers.

Results: Mode of inheritance in our RLS family was compatible with an autosomal dominant pattern, and disease onset was mainly in childhood or adolescence. We excluded linkage to the RLS1, RLS2, RLS4, and RLS5 loci. However, we identified a likely new RLS gene locus (RLS3*) on chromosome 9p with a maximum lod score of 3.60 generated by model-based multipoint linkage analysis. A haplotype flanked by D9S974 and D9S1118 in a 9.9-Mb region, centromeric to RLS3, was shared by all 12 investigated patients. In addition, 11 of them carried a common haplotype extending telomeric to D9S2189 that is located within RLS3.

Conclusions: We demonstrate linkage to a locus on chromosome 9p that is probably distinct from RLS3. Our family with a rather homogeneous phenotype and very early disease onset represents a unique opportunity to further elucidate the genetic causes of the frequent restless leg syndrome.

Abbreviations: bp = base pair; NA = not applicable; PLMS = periodic limb movements in sleep; RLS = restless leg syndrome.

Editorial, page 664

e-Pub ahead of print on November 21, 2007, at www.neurology.org.

* These authors contributed equally to the work presented in this article.

Supported by the Volkswagen Foundation, a research grant from the Deutsche Forschungsgemeinschaft (HE 4547/1-1, STE 421/2-1), and scholarships from the Novartis Foundation for Therapeutic Medicine and the Gottlieb Daimler and Karl Benz Foundation.

Disclosure: The authors report no conflicts of interest.

Received December 14, 2006. Accepted in final form May 8, 2007.