FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2021018204> ?p ?o ?g. }

• W2021018204 endingPage "723" @default.
• W2021018204 startingPage "716" @default.
• W2021018204 abstract "Restless legs syndrome (RLS) is a common neurological condition with three loci (12q, 14q, and 9p) described so far, although none of these genes has yet been identified. We report a genomewide linkage scan of patients with RLS (n=37) assessed in a population isolate (n=530) of South Tyrol (Italy). Using both nonparametric and parametric analyses, we initially obtained suggestive evidence of a novel locus on chromosome 2q, with nominal evidence of linkage on chromosomes 5p and 17p. Follow-up genotyping yielded significant evidence of linkage (nonparametric LOD score 5.5, P≤.0000033; heterogeneity LOD score 5.1; α=1.0) on chromosome 2q. Three families (S01, S05, and S016) were shown to descend from a common founder couple. A disease haplotype shared between family S01 and family S05 defines a candidate region of 8.2 cM; in addition, the single affected individual in family S016 shares three linked alleles at neighboring markers, which suggests a reduced candidate interval of only 1.6 cM. Two-point linkage analysis in this 10-generation pedigree provided significant evidence of a novel RLS locus in this region (LOD score 4.1). These findings reemphasize the genetic heterogeneity of the disorder and strongly support the identification of a novel locus for RLS on chromosome 2q. Restless legs syndrome (RLS) is a common neurological condition with three loci (12q, 14q, and 9p) described so far, although none of these genes has yet been identified. We report a genomewide linkage scan of patients with RLS (n=37) assessed in a population isolate (n=530) of South Tyrol (Italy). Using both nonparametric and parametric analyses, we initially obtained suggestive evidence of a novel locus on chromosome 2q, with nominal evidence of linkage on chromosomes 5p and 17p. Follow-up genotyping yielded significant evidence of linkage (nonparametric LOD score 5.5, P≤.0000033; heterogeneity LOD score 5.1; α=1.0) on chromosome 2q. Three families (S01, S05, and S016) were shown to descend from a common founder couple. A disease haplotype shared between family S01 and family S05 defines a candidate region of 8.2 cM; in addition, the single affected individual in family S016 shares three linked alleles at neighboring markers, which suggests a reduced candidate interval of only 1.6 cM. Two-point linkage analysis in this 10-generation pedigree provided significant evidence of a novel RLS locus in this region (LOD score 4.1). These findings reemphasize the genetic heterogeneity of the disorder and strongly support the identification of a novel locus for RLS on chromosome 2q. Restless legs syndrome (RLS [MIM 102300]) is a common and frequently underdiagnosed neurological disorder. Estimated prevalence rates vary widely, from 2% to 15% of the general population.1Allen RP Walters AS Montplaisir J Hening W Myers A Bell TJ Ferini-Strambi L Restless legs syndrome prevalence and impact: REST general population study.Arch Intern Med. 2005; 165: 1286-1292Crossref PubMed Scopus (909) Google Scholar, 2Tison F Crochard A Leger D Bouee S Lainey E El Hasnaoui A Epidemiology of restless legs syndrome in French adults: a nationwide survey: the INSTANT Study.Neurology. 2005; 65: 239-246Crossref PubMed Scopus (256) Google Scholar RLS can be diagnosed by the clinical presence of four essential criteria developed by the International Restless Legs Syndrome Study Group3Walters AS International Restless Legs Syndrome Study Group Toward a better definition of the restless legs syndrome.Mov Disord. 1995; 10: 634-642Crossref PubMed Scopus (1029) Google Scholar and revised in a National Institutes of Health consensus statement4Allen RP Picchietti D Hening WA Trenkwalder C Walters AS Montplaisi J 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. 2003; 4: 101-119Abstract Full Text Full Text PDF PubMed Scopus (2444) Google Scholar: (1) an urge to move the legs, usually accompanied by uncomfortable sensations (paresthesias, dysesthesias), (2) occurrence of symptoms primarily while at rest, (3) partial or total relief with movement, and (4) worsening of symptoms in the evening or night. RLS is generally classified into idiopathic and symptomatic forms. In idiopathic RLS, which includes both sporadic and familial cases, results of physical and neurological examinations are normal. Symptomatic (secondary) forms can be caused by many conditions, such as polyneuropathy, iron deficiency, anemia, kidney disease, or thyroid dysfunction.5Trenkwalder C Paulus W Walters AS The restless legs syndrome.Lancet Neurol. 2005; 4: 465-475Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar A substantial genetic contribution to idiopathic RLS has been consistently recognized from population and family studies. A family history of RLS was described in 40%–90% of patients,6Winkelmann J Ferini-Strambi L Genetics of restless legs syndrome.Sleep Med Rev. 2006; 10: 179-183Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar and the high concordance rate of 83.3% between identical twins was reported.7Ondo WG Vuong KD Wang Q Restless legs syndrome in monozygotic twins: clinical correlates.Neurology. 2000; 55: 1404-1406Crossref PubMed Google Scholar In a set of multiplex families from North America, the heritability of RLS was estimated to be 0.60.8Chen S Ondo WG 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. 2004; 74: 876-885Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Most reports of familial cases have suggested autosomal dominant transmission,9Winkelmann J The genetics of restless legs syndrome.Sleep Med Suppl. 2002; 3: S9-S12Abstract Full Text Full Text PDF Scopus (19) Google Scholar although broad intrafamilial phenotypic expressivity, with a variable age at onset and disease course, has been reported.10Walters AS Picchietti D Hening W Lazzarini A Variable expressivity in familial restless legs syndrome.Arch Neurol. 1990; 47: 1219-1220Crossref PubMed Scopus (90) Google Scholar To date, linkage studies have identified three loci on chromosomes—12q,11Desautels A Turecki G Montplaisir J Sequeira A Verner A Rouleau GA Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q.Am J Hum Genet. 2001; 69: 1266-1270Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar 14q,12Bonati MT Ferini-Strambi L Aridon P Oldani A Zucconi M Casari G Autosomal dominant restless legs syndrome maps on chromosome 14q.Brain. 2003; 126: 1485-1492Crossref PubMed Scopus (234) Google Scholar and 9p8Chen S Ondo WG 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. 2004; 74: 876-885Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar—in RLS-affected families from different populations. However, no disease-causing gene has yet been identified. These molecular findings, together with the reported variable expressivity of the phenotype, suggest substantial genetic and clinical heterogeneity of RLS. One way to reduce the genetic complexity, and potentially also the environmental heterogeneity, is the use of isolated populations. Here, we report a genomewide linkage analysis of patients with RLS collected from one small village that has conserved a high degree of isolation in the western Alps of South Tyrol (Italy). It reveals increased background linkage disequilibrium (LD) due to the peculiar demographic history that has led to genetic drift and founder effects.13Marroni F (2006) Population isolates in South Tyrol and their value for genetic dissection of complex diseases. Ann Hum Genet (in press)Google Scholar The village originates from an old settlement, has few founders, and experienced slow expansion over time. Apart from these demographic characteristics relating to the population history and therefore associated with the genetic background, historical documents allowed the reconstruction of extended pedigrees as far back as the 17th century.14Vogl 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 Restless legs syndrome: epidemiological and clinicogenetic study in a South Tyrolean population isolate.Mov Disord. 2006; (electronically published May 9, 2006) (accessed August 3, 2006)(http://www3.interscience.wiley.com/cgi-bin/fulltext/112608030/HTMLSTART)PubMed Google Scholar The study is part of a larger ongoing genomic research program (GenNova) investigating the South Tyrolean population. The RLS phenotype was clinically assessed in two steps. First, a detailed questionnaire-based interview and a medical screening exam of 530 voluntary study participants were performed. The questionnaire included the four minimal criteria for RLS.3Walters AS International Restless Legs Syndrome Study Group Toward a better definition of the restless legs syndrome.Mov Disord. 1995; 10: 634-642Crossref PubMed Scopus (1029) Google Scholar A blood sample was taken for DNA extraction and routine clinical chemistry analysis. In the second step, subjects presumed to have RLS were reexamined by a movement-disorder specialist. A standardized neurological examination was performed, and a detailed interview covered age at onset of symptoms, family history, localization of symptoms, lateralization, and sleep problems. The severity of symptoms was rated using both the International Restless Legs Syndrome Rating Scale (IRLS)15Walters AS LeBrocq C Dhar A Hening W Rosen R Allen RP Trenkwalder C Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome.Sleep Med. 2003; 4: 121-132Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar and the Johns Hopkins Restless Legs Severity Scale (JHRLSS).16Allen RP Earley CJ Validation of the Johns Hopkins Restless Legs Severity Scale.Sleep Med. 2001; 2: 239-242Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar The final diagnosis of RLS was made according to currently accepted diagnostic criteria.4Allen RP Picchietti D Hening WA Trenkwalder C Walters AS Montplaisi J 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. 2003; 4: 101-119Abstract Full Text Full Text PDF PubMed Scopus (2444) Google Scholar Secondary causes of RLS were determined by electrophysiology and biochemical tests, including laboratory parameters for iron metabolism; renal, hepatic and endocrine function; and diabetes. None of the subjects reported the use of medication known to affect sleep or sensory or motor functions. Thirty-seven patients with idiopathic RLS whose ancestry was from this village were identified; three patients (members of families S01, S02, and S03) were designated as having uncertain status. Nine individuals with symptoms associated with secondary RLS were excluded from the present study. Twelve affected individuals clustered in one large and extended family (S01), and 17 other families consisted of 1–5 affected members each. Six of the families (S01, S02, S03, S05, S06, and S08) were informative for linkage; the remaining 12 were subsequently included for haplotype analysis. Of the 18 families, 61 clinically unaffected members were available for the study. Disease status of 31 unaffected individuals was set as “unknown,” because they participated only in the first step of the phenotype assessment. Of 14 fully assessed healthy members of S01, one was set as “unknown,” because his age was lower than the mean age at onset plus 1 SD, as obtained from the sample of affected individuals in this family. Study participants gave written informed consent. The study was approved by the local ethics committee. We performed a 4-cM genomewide linkage scan on DNA from all 530 study participants, using 1,000 microsatellite markers (i.e., STRs) genotyped at deCODE Genetics. The data were analyzed by multipoint model-free and parametric linkage analyses with use of the software GENEHUNTER 2.1.17Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar For the model-free analysis, the NPL score was calculated using the Sall statistic to estimate the allele sharing among all affected individuals in the pedigrees. Because of program memory constraints, 3 affected and 13 unaffected individuals of the largest family (S01) were dropped from the analysis. The parametric analysis was performed under the assumption of an autosomal dominant model, which allowed for locus heterogeneity. The disease-allele frequency was set at 0.001, and penetrances were set at 0.7, 0.7, and 0.01 for homozygotes, heterozygotes, and noncarriers, respectively. Marker-allele frequencies were estimated on the basis of the 530 study participants, and recombination rates for males and females were assumed to be equal. The results of the genomewide multipoint nonparametric and parametric analyses are presented in figure 1. The highest signal among the 22 scanned autosomes was observed for marker D2S117, with an NPL score of 3.79 (P=.0042) and a LOD−1 interval of 18.47 cM. The highest heterogeneity LOD (HLOD) score (2.88) was detected between markers D2S311 and D2S116 (α=1.0). Despite the fact that linkage analysis in the presence of heterogeneity is robust and powerful for complex diseases, the estimate of the proportion of linked families, α, is not accurate in this circumstance.18Hodge SE Vieland VJ Greenberg DA HLODs remain powerful tools for detection of linkage in the presence of genetic heterogeneity.Am J Hum Genet. 2002; 70: 556-559Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 19Vieland VJ Logue M HLODs, trait models, and ascertainment: implications of admixture for parameter estimation and linkage detection.Hum Hered. 2002; 53: 23-35Crossref PubMed Scopus (32) Google Scholar, 20Whittemore AS Halpern J Problems in the definition, interpretation, and evaluation of genetic heterogeneity.Am J Hum Genet. 2001; 68: 457-465Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The largest multigenerational family (S01) contributed the bulk of the score for the linkage peak on chromosome 2q (LOD score of 2.34 at marker D2S117 and corresponding NPL score of 12.5 [P=.0019]). In addition, two other regions of the genome showed nominal evidence of linkage to RLS in the parametric multipoint analysis: D5S2848 (HLOD 1.2; α=0.43) and D17S804 (HLOD 1.0; α=1.0).Figure 1Results of the genomewide scan for each chromosome. The black curve represents NPL scores, the gray curve represents HLOD scores, and the dotted curve represents STR marker informativity. Genetic distances are based on the deCODE Genetic map.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To fine map the chromosome 2 candidate region, we chose a set of 11 additional microsatellite markers (D2S2392, D2S2289, D2S325, D2S2242, D2S2208, D2S154, D2S2178, D2S2274, D2S1369, D2S157, and D2S371) from the University of California–Santa Cruz (UCSC) Genome Browser 2004 human genome assembly (UCSC Genome Bioinformatics). Marker order was based on the physical map, and genetic distances were based on the sex-averaged Marshfield genetic map (Center for Medical Genetics Web site) (fig. 2). We estimated allele frequencies for these markers from 88 unrelated (during at least the last 3 generations) individuals of the same village. We genotyped these markers in 101 individuals from the 18 RLS-affected families, using a 3100 Sequencer (Applied Biosystems), and we assigned genotypes using Genemapper version 3.7 software. For the detailed mapping of the chromosome 2 candidate region, we calculated multipoint model-free and parametric LOD scores using SIMWALK2,21Sobel E Lange K Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics.Am J Hum Genet. 1996; 58: 1323-1337PubMed Google Scholar, 22Sobel E Sengul H Weeks DE Multipoint estimation of identity-by-descent probabilities at arbitrary positions among marker loci on general pedigrees.Hum Hered. 2001; 52: 121-131Crossref PubMed Scopus (145) Google Scholar which allowed the inclusion of all individuals of S01. A two-point analysis was performed using the MLINK program (LINKAGE software package).23Lathrop GM Lalouel JM Julier C Ott J Multilocus linkage analysis in humans: detection of linkage and estimation of recombination.Am J Hum Genet. 1985; 37: 482-498PubMed Google Scholar The same parameters as in the genomewide multipoint analysis were used. The SIMWALK2 analysis (fig. 3) provided strong evidence of a candidate region between markers D2S311 and D2S317 (11.7 cM), with a peak NPL score of 5.5 (P≤3.33×10−6) and a peak HLOD score of 5.1 at markers D2S325, D2S1369, and D2S157. These data, which exceed the genomewide significance level defined by Lander and Kruglyak (LOD 3.6; P=.000022),24Lander E Kruglyak L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar indicate the presence of an RLS locus in this region of chromosome 2q. We next used genotype data for 20 markers on chromosome 2q to examine the pattern of haplotype transmission for all individuals in the 18 families, in an attempt to identify haplotype sharing among the 37 idiopathic RLS cases. We found that a common 7-marker haplotype (11-6-5-8-8-6-5) in the chromosome 2q33 region is shared identical by descent by all 15 affected members of families S01 and S05 (fig. 2). Obligate recombination events defined a candidate region of 8.2 cM between markers D2S311 and D2S2208. Notably, the single affected individual of family S016 shares the alleles of the disease-chromosome haplotype for only the three distal markers (8-6-5) (fig. 2). From genealogical studies, we found that families S01, S05, and S016 descended from a common founder couple 10 generations ago (fig. 2). Two-point linkage analysis of this large genealogy resulted in a maximum LOD score of 4.1 at θ=0.0 at marker D2S2242. The remaining 15 families do not descend from a common ancestor; in those families, no common haplotype was observed, and the maximum LOD score we obtained was 0.4 in S06. The three families S01, S05, and S016 also share a common haplotype for the chromosome 5p region, with the exception of three affected members of S01 (VIII-7, VIII-11, and IX-22), but not for the chromosome 17p region. Proximal and distal recombinants allowed us to define the common genomic region as spanning 11.8 cM (between markers D5S1954 and D5S2848), although the potential significance of this region is unclear. Clinical data from all 16 affected members of families S01, S05, and S016, together with the haplotype status on chromosome 2q33 and chromosome 5p15-p14, are reported in table 1.Table 1Clinical Features of RLS in the 16 Patients of Families S01, S05, and S016Age (years)Family and PatientSexAt StudyAt OnsetSeverity (IRLS/JHRLSS)aNA = not assessed.AwakeningsInvolvement of Upper LimbsLateralization of SymptomsCourseHaplotype Status (c2q/c5p)bIndividuals sharing the haplotypes on chromosomes 2q and 5p are identified with +/+; those sharing the haplotype only on chromosome 2q are identified with +/−.S01: VIII-1F701232/2−−LeftProgressive+/+ VIII-2F761231/3++−Progressive+/+ VIII-5M7960NA−−LeftStable+/+ VIII-7M683010/1−−−Remission+/− VIII-11M635011/2−−RightStable+/− IX-14M432018/2+−−Progressive+/+ IX-16M391515/2++RightRemission+/+ IX-17F514120/2++−Stable+/+ IX-19F342910/1−−LeftProgressive+/+ IX-22M36317/2−−−Stable+/− IX-24M27257/2++−Stable+/+ X-27F14136/1−−−Stable+/+S05: VIII-1M644913/1+−−Remission+/+ VIII-2F595212/2−−−Stable+/+ VIII-3M6358NA+−−Stable+/+S016: IX-3M39358/1−−−Stable+/+a NA = not assessed.b Individuals sharing the haplotypes on chromosomes 2q and 5p are identified with +/+; those sharing the haplotype only on chromosome 2q are identified with +/−. Open table in a new tab We performed our model-based analyses with the assumption of autosomal dominant inheritance with a reduced penetrance of 70%. Formal segregation analysis in a large set of families has argued for a single autosomal dominant major gene with a multifactorial component in families with early disease onset (i.e., onset age of <30 years).25Winkelmann J Muller-Myhsok B Wittchen HU Hock B Prager M Pfister H Strohle A Eisensehr I Dichgans M Gasser T Trenkwalder C Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families.Ann Neurol. 2002; 52: 297-302Crossref PubMed Scopus (222) Google Scholar The reported penetrance value varies from full penetrance26Lazzarini A Walters AS Hickey K Coccagna G Lugaresi E Ehrenberg BL Picchietti DL Brin MF Stenroos ES Verrico T Johnson WG Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees.Mov Disord. 1999; 14: 111-116Crossref PubMed Scopus (94) Google Scholar to 70% for individuals showing only periodic leg movements during sleep but who are otherwise without RLS symptoms.27Picchietti DL Underwood DJ Farris WA Walters AS Shah MM Dahl RE Trubnick LJ Bertocci MA Wagner M Hening WA Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder.Mov Disord. 1999; 14: 1000-1007Crossref PubMed Scopus (269) Google Scholar Additionally, in children and mildly affected individuals with intermittent symptoms, it can be difficult to recognize the RLS phenotype. To overcome this possible drawback, we opted for a reduced penetrance in our linkage analysis. However, reanalysis of our data with different model parameters, such as increasing the estimates of penetrance, did not substantially change the results (e.g., two-point LOD score of 3.3 with 0.9 penetrance and 0.01 phenocopies). Similarly, an affected-only analysis yielded a two-point LOD score of 3.4. Three other loci have been reported elsewhere for RLS.8Chen S Ondo WG 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. 2004; 74: 876-885Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11Desautels A Turecki G Montplaisir J Sequeira A Verner A Rouleau GA Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q.Am J Hum Genet. 2001; 69: 1266-1270Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 12Bonati MT Ferini-Strambi L Aridon P Oldani A Zucconi M Casari G Autosomal dominant restless legs syndrome maps on chromosome 14q.Brain. 2003; 126: 1485-1492Crossref PubMed Scopus (234) Google Scholar Linkage to the chromosome 12q and chromosome 14q loci was recently replicated.28Desautels A Turecki G Montplaisir J Xiong L Walters AS Ehrenberg BL Brisebois K Desautels AK Gingras Y Johnson WG Lugaresi E Coccagna G Picchietti DL Lazzarini A Rouleau GA Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity.Arch Neurol. 2005; 62: 591-596Crossref PubMed Scopus (95) Google Scholar, 29Levchenko A Montplaisir JY Dube MP Riviere JB St Onge J Turecki G Xiong L Thibodeau P Desautels A Verlaan DJ Rouleau GA The 14q restless legs syndrome locus in the French Canadian population.Ann Neurol. 2004; 55: 887-891Crossref PubMed Scopus (65) Google Scholar, 30Winkelmann J Lichtner P Putz B Trenkwalder C Hauk S Meitinger T Strom T Muller-Myhsok B Evidence for further genetic locus heterogeneity and confirmation of RLS-1 in restless legs syndrome.Mov Disord. 2006; 21: 28-33Crossref PubMed Scopus (66) Google Scholar On the other hand, linkage to chromosome 12q could be replicated neither in two South Tyrolean families31Kock N Culjkovic B Maniak S Schilling K Müller B Zühlke C Ozelius L Klein C Pramstaller PP Kramer PL Mode of inheritance and susceptibility locus for restless legs syndrome, on chromosome 12q.Am J Hum Genet. 2002; 71: 205-208Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar nor in two northern Italian families.32Ferini-Strambi L Bonati MT Oldani A Aridon P Zucconi M Casari G Genetics in restless legs syndrome.Sleep Med. 2004; 5: 301-304Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Furthermore, when the same village investigated in the present report was studied, no evidence of linkage of RLS was found14Vogl 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 Restless legs syndrome: epidemiological and clinicogenetic study in a South Tyrolean population isolate.Mov Disord. 2006; (electronically published May 9, 2006) (accessed August 3, 2006)(http://www3.interscience.wiley.com/cgi-bin/fulltext/112608030/HTMLSTART)PubMed Google Scholar to the three RLS loci described elsewhere.8Chen S Ondo WG 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. 2004; 74: 876-885Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 11Desautels A Turecki G Montplaisir J Sequeira A Verner A Rouleau GA Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q.Am J Hum Genet. 2001; 69: 1266-1270Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 12Bonati MT Ferini-Strambi L Aridon P Oldani A Zucconi M Casari G Autosomal dominant restless legs syndrome maps on chromosome 14q.Brain. 2003; 126: 1485-1492Crossref PubMed Scopus (234) Google Scholar These data, together with the substantial variability of symptoms, suggest that RLS may have a polygenic basis, with contributions of major genes, modifier genes, and complex interactions of genes and environment. In geographically or culturally isolated populations that descended from a small number of founders, a more restricted number of susceptibility loci and disease alleles at each locus can be reasonably expected. In fact, the RLS locus on 12q was identified in the French Canadian population, for which a founder effect has been described.11Desautels A Turecki G Montplaisir J Sequeira A Verner A Rouleau GA Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q.Am J Hum Genet. 2001; 69: 1266-1270Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Recently, it was shown that 31.6% of the total number of families identified in the French Canadian population were linked to the chromosome 12q locus.28Desautels A Turecki G Montplaisir J Xiong L Walters AS Ehrenberg BL Brisebois K Desautels AK Gingras Y Johnson WG Lugaresi E Coccagna G Picchietti DL Lazzarini A Rouleau GA Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity.Arch Neurol. 2005; 62: 591-596Crossref PubMed Scopus (95) Google Scholar LD and historical data from the South Tyrol region and the small isolated village suggest that individuals may share a small number of disease alleles.13Marroni F (2006) Population isolates in South Tyrol and their value for genetic dissection of complex diseases. Ann Hum Genet (in press)Google Scholar The shared disease haplotype in related families S01 and S05 effectively narrows the candidate region to 8.2 cM. Using the program PHASE,33Stephens M Smith NJ Donnelly P A new statistical method for haplotype reconstruction from population data.Am J Hum Genet. 2001; 68: 978-989Abstract Full Text Full Text PDF PubMed Scopus (6192) Google Scholar which has been shown to provide accurate estimates of haplotype frequencies from population data,34Marroni F Toni C Pennato B Tsai YY Duggal P Bailey-Wilson JE Presciuttini S Haplotypic structure of the X chromosome in the COGA population sample and the quality of its reconstruction by extant software packages.BMC Genet Suppl. 2005; 6: S77Crossref PubMed Scopus (8) Google Scholar we estimated haplotype frequencies from 88 unrelated individuals in the village. The extended shared haplotype from families S01 and S05 was present in only 0.93% of the control individuals, which strongly indicates that its shared presence in the affected individuals points to the presence of an RLS disease allele. By contrast, the population frequency of the 3-marker haplotype identified in the distantly related S016 was 7%, which makes reliance on this single individual for definition of a reduced candidate region of 1.6 cM more risky. In the 1.6-cM region, there are currently 11 annotated genes, of which 3 are predicted genes with unknown function. Among some plausible candidate genes, we recognized (1) CPO with carboxypeptidase activity, (2) CREB1, which encodes a cAMP-responsive element-binding protein, and (3) KLF7, Kruppel-like factor 7, with transcription factor activity. The larger 8.2-cM interval contains >100 annotated genes. The haplotype frequency of the chromosome 5 region was estimated to be 23%, suggesting that this interval does not play a major role in the etiology of RLS in our population. In summary, our linkage data encompassing 37 idiopathic RLS cases from this isolated village and the haplotype-sharing data of patients of three families provide strong evidence for the identification of a new major susceptibility locus for RLS at 2q33 in a South Tyrolean population isolate. The novel locus provides further evidence that RLS is a genetically highly heterogeneous disorder. In addition, it can be expected that the identification of the underlying gene defect at 2q33 will contribute to our current understanding of the underlying biological mechanisms of RLS. The authors are grateful to the study participants, the primary care physician of the village (Stocker Raffaela), and the Hospital of Silandro (Department of Laboratory Medicine), for their participation and collaboration in this research project. We thank Sara Pedrotti and Agatha Eisendle for technical support. We gratefully acknowledge P. Michael Conneally and Tatiana Foroud, for helpful comments on the manuscript. The study was supported by the Ministry of Health of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation (support to P.P.P.), the South Tyrolean Parkinson Disease Association (support to P.P.P.), and by the Volkswagen Foundation (support to C.K.)." @default.
• W2021018204 created "2016-06-24" @default.
• W2021018204 creator A5021342200 @default.
• W2021018204 creator A5024773860 @default.
• W2021018204 creator A5028897369 @default.
• W2021018204 creator A5043180144 @default.
• W2021018204 creator A5044329623 @default.
• W2021018204 creator A5059718529 @default.
• W2021018204 creator A5068037007 @default.
• W2021018204 creator A5083188517 @default.
• W2021018204 date "2006-10-01" @default.
• W2021018204 modified "2023-10-10" @default.
• W2021018204 title "Linkage Analysis Identifies a Novel Locus for Restless Legs Syndrome on Chromosome 2q in a South Tyrolean Population Isolate" @default.
• W2021018204 cites W1519466388 @default.
• W2021018204 cites W1549470101 @default.
• W2021018204 cites W1964109797 @default.
• W2021018204 cites W1968101249 @default.
• W2021018204 cites W1976741643 @default.
• W2021018204 cites W1977809194 @default.
• W2021018204 cites W1979385900 @default.
• W2021018204 cites W1995365393 @default.
• W2021018204 cites W1996821936 @default.
• W2021018204 cites W1998185782 @default.
• W2021018204 cites W2006353519 @default.
• W2021018204 cites W2017280547 @default.
• W2021018204 cites W2029499842 @default.
• W2021018204 cites W2035099377 @default.
• W2021018204 cites W2044737368 @default.
• W2021018204 cites W2047116259 @default.
• W2021018204 cites W2056984548 @default.
• W2021018204 cites W2068376478 @default.
• W2021018204 cites W2072667894 @default.
• W2021018204 cites W2076649284 @default.
• W2021018204 cites W2079325113 @default.
• W2021018204 cites W2079367745 @default.
• W2021018204 cites W2083862362 @default.
• W2021018204 cites W2086059732 @default.
• W2021018204 cites W2091605545 @default.
• W2021018204 cites W2107871825 @default.
• W2021018204 cites W2110755408 @default.
• W2021018204 cites W2112789922 @default.
• W2021018204 cites W2113576922 @default.
• W2021018204 cites W2123470267 @default.
• W2021018204 cites W2126303471 @default.
• W2021018204 cites W2162410770 @default.
• W2021018204 cites W2172104540 @default.
• W2021018204 cites W2408799309 @default.
• W2021018204 doi "https://doi.org/10.1086/507875" @default.
• W2021018204 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1592574" @default.
• W2021018204 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16960808" @default.
• W2021018204 hasPublicationYear "2006" @default.
• W2021018204 type Work @default.
• W2021018204 sameAs 2021018204 @default.
• W2021018204 citedByCount "98" @default.
• W2021018204 countsByYear W20210182042012 @default.
• W2021018204 countsByYear W20210182042013 @default.
• W2021018204 countsByYear W20210182042014 @default.
• W2021018204 countsByYear W20210182042015 @default.
• W2021018204 countsByYear W20210182042017 @default.
• W2021018204 countsByYear W20210182042018 @default.
• W2021018204 countsByYear W20210182042019 @default.
• W2021018204 countsByYear W20210182042020 @default.
• W2021018204 countsByYear W20210182042021 @default.
• W2021018204 countsByYear W20210182042022 @default.
• W2021018204 countsByYear W20210182042023 @default.
• W2021018204 crossrefType "journal-article" @default.
• W2021018204 hasAuthorship W2021018204A5021342200 @default.
• W2021018204 hasAuthorship W2021018204A5024773860 @default.
• W2021018204 hasAuthorship W2021018204A5028897369 @default.
• W2021018204 hasAuthorship W2021018204A5043180144 @default.
• W2021018204 hasAuthorship W2021018204A5044329623 @default.
• W2021018204 hasAuthorship W2021018204A5059718529 @default.
• W2021018204 hasAuthorship W2021018204A5068037007 @default.
• W2021018204 hasAuthorship W2021018204A5083188517 @default.
• W2021018204 hasBestOaLocation W20210182041 @default.
• W2021018204 hasConcept C104317684 @default.
• W2021018204 hasConcept C122735190 @default.
• W2021018204 hasConcept C142870003 @default.
• W2021018204 hasConcept C2908647359 @default.
• W2021018204 hasConcept C2993098900 @default.
• W2021018204 hasConcept C30481170 @default.
• W2021018204 hasConcept C31266012 @default.
• W2021018204 hasConcept C54355233 @default.
• W2021018204 hasConcept C71924100 @default.
• W2021018204 hasConcept C84597430 @default.
• W2021018204 hasConcept C86803240 @default.
• W2021018204 hasConcept C99454951 @default.
• W2021018204 hasConceptScore W2021018204C104317684 @default.
• W2021018204 hasConceptScore W2021018204C122735190 @default.
• W2021018204 hasConceptScore W2021018204C142870003 @default.
• W2021018204 hasConceptScore W2021018204C2908647359 @default.
• W2021018204 hasConceptScore W2021018204C2993098900 @default.
• W2021018204 hasConceptScore W2021018204C30481170 @default.
• W2021018204 hasConceptScore W2021018204C31266012 @default.
• W2021018204 hasConceptScore W2021018204C54355233 @default.
• W2021018204 hasConceptScore W2021018204C71924100 @default.
• W2021018204 hasConceptScore W2021018204C84597430 @default.
• W2021018204 hasConceptScore W2021018204C86803240 @default.

• next