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• W2024794315 abstract "A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder. A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder. Parkinson’s disease (PD) is a frequent neurodegenerative disorder with a prevalence of ∼2% in persons >65 years old (Elbaz et al. Elbaz et al., 1999Elbaz A Grigoletto F Baldereschi M Breteler MM Manubens-Bertran JM Lopez-Pousa S Dartigues JF Alperovitch A Tzourio C Rocca WA Familial aggregation of Parkinson's disease: a population-based case-control study in Europe. Europarkinson Study Group.Neurology. 1999; 52: 1876-1882Crossref PubMed Google Scholar). The main clinical features are rigidity, bradykinesia, and tremor, associated with a good response to levodopa. The disorder is caused by a massive loss of dopaminergic neurons in the pars compacta of the substantia nigra and is characterized by the presence of Lewy bodies (cytoplasmic eosinophilic hyaline inclusions) (Fearnley and Lees Fearnley and Lees, 1991Fearnley JM Lees AJ Ageing and Parkinson's disease: substantia nigra regional selectivity.Brain. 1991; 114: 2283-2301Crossref PubMed Scopus (2412) Google Scholar). Genetic risk factors are probably involved in the pathogenesis of Parkinson’s disease (de Silva et al. de Silva et al., 2000de Silva HR Khan NL Wood NW The genetics of Parkinson's disease.Curr Opin Genet Dev. 2000; 10: 292-298Crossref PubMed Scopus (73) Google Scholar), and several families with clearly established monogenic inheritance have been reported. The majority of such cases are caused by mutations in the parkin gene, which result in autosomal recessive early-onset parkinsonism (MIM 600116) (Hattori et al. Hattori et al., 1998aHattori N Kitada T Matsumine H Asakawa S Yamamura Y Yoshino H Kobayashi T Yokochi M Wang M Yoritaka A Kondo T Kuzuhara S Nakamura S Shimizu N Mizuno Y Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals.Ann Neurol. 1998; 44: 935-941Crossref PubMed Scopus (281) Google Scholar, Hattori et al., 1998bHattori N Matsumine H Asakawa S Kitada T Yoshino H Elibol B Brookes AJ Yamamura Y Kobayashi T Wang M Yoritaka A Minoshima S Shimizu N Mizuno Y Point mutations (Thr240Arg and Gln311Stop [correction of Thr240Arg and Ala311Stop]) in the parkin gene.Biochem Biophys Res Commun. 1998; 249: 754-758Crossref PubMed Scopus (171) Google Scholar; Kitada et al. Kitada et al., 1998Kitada T Asakawa S Hattori N Matsumine H Yamamura Y Minoshima S Yokochi M Mizuno Y Shimizu N Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature. 1998; 392: 605-608Crossref PubMed Scopus (3891) Google Scholar; Leroy et al. Leroy et al., 1998aLeroy E Anastasopoulos D Konitsiotis S Lavedan C Polymeropoulos MH Deletions in the parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease.Hum Genet. 1998; 103: 424-427Crossref PubMed Scopus (120) Google Scholar; Lücking et al. Lücking et al., 1998Lücking CB Abbas N Durr A Bonifati V Bonnet AM de Broucker T De Michele G Wood NW Agid Y Brice A Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group.Lancet. 1998; 352: 1355-1356Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar; Abbas et al. Abbas et al., 1999Abbas N Lücking CB Ricard S Durr A Bonifati V De Michele G Bouley S Vaughan JR Gasser T Marconi R Broussolle E Brefel-Courbon C Harhangi BS Oostra BA Fabrizio E Bohme GA Pradier L Wood NW Filla A Meco G Denefle P Agid Y Brice A A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.Hum Mol Genet. 1999; 8: 567-574Crossref PubMed Scopus (470) Google Scholar). The number of patients with mutations in the α-synuclein (Polymeropoulos et al. Polymeropoulos et al., 1997Polymeropoulos MH Lavedan C Leroy E Ide SE Dehejia A Dutra A Pike B Root H Rubenstein J Boyer R Stenroos ES Chandrasekharappa S Athanassiadou A Papapetropoulos T Johnson WG Lazzarini AM Duvoisin RC Di Iorio G Golbe LI Nussbaum RL Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.Science. 1997; 276: 2045-2047Crossref PubMed Scopus (6117) Google Scholar) or ubiquitin carboxy-terminal hydrolase (UCH)–L1 genes (Leroy et al. Leroy et al., 1998bLeroy E Boyer R Auburger G Leube B Ulm G Mezey E Harta G Brownstein MJ Jonnalagada S Chernova T Dehejia A Lavedan C Gasser T Steinbach PJ Wilkinson KD Polymeropoulos MH The ubiquitin pathway in Parkinson's disease.Nature. 1998; 395: 451-452Crossref PubMed Scopus (1330) Google Scholar) is much smaller. The phenotype associated with parkin gene mutations is variable but is usually characterized by early-onset parkinsonism and slow disease progression (Ishikawa and Tsuji Ishikawa and Tsuji, 1996Ishikawa A Tsuji S Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism.Neurology. 1996; 47: 160-166Crossref PubMed Scopus (216) Google Scholar; Lücking et al. Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar). Postmortem examinations reveal massive loss of dopaminergic neurons in the substantia nigra pars compacta and the absence of Lewy bodies, results suggesting that the pathologic process may differ from that of idiopathic Parkinson’s disease (Takahashi et al. Takahashi et al., 1994Takahashi H Ohama E Suzuki S Horikawa Y Ishikawa A Morita T Tsuji S Ikuta F Familial juvenile parkinsonism: clinical and pathologic study in a family.Neurology. 1994; 44: 437-441Crossref PubMed Google Scholar; Mori et al. Mori et al., 1998Mori H Kondo T Yokochi M Matsumine H Nakagawa-Hattori Y Miyake T Suda K Mizuno Y Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q.Neurology. 1998; 51: 890-892Crossref PubMed Scopus (309) Google Scholar; van de Warrenburg, Van de Warrenburg et al., in pressVan de Warrenburg BPC, Lammens M, Lücking CB, Denefle P, Wesseling P, Booij J, Praamstra P, Quinn N, Brice A, Horstink MWIM. Parkinsonism associated with parkin gene mutations: clinical and pathological abnormalities in a Dutch family. Neurology (in press)Google Scholar). A wide variety of mutations in the parkin gene have been detected, including exon deletions and duplications, as well as point mutation (Hattori et al. Hattori et al., 1998aHattori N Kitada T Matsumine H Asakawa S Yamamura Y Yoshino H Kobayashi T Yokochi M Wang M Yoritaka A Kondo T Kuzuhara S Nakamura S Shimizu N Mizuno Y Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals.Ann Neurol. 1998; 44: 935-941Crossref PubMed Scopus (281) Google Scholar, Hattori et al., 1998bHattori N Matsumine H Asakawa S Kitada T Yoshino H Elibol B Brookes AJ Yamamura Y Kobayashi T Wang M Yoritaka A Minoshima S Shimizu N Mizuno Y Point mutations (Thr240Arg and Gln311Stop [correction of Thr240Arg and Ala311Stop]) in the parkin gene.Biochem Biophys Res Commun. 1998; 249: 754-758Crossref PubMed Scopus (171) Google Scholar Kitada et al. Kitada et al., 1998Kitada T Asakawa S Hattori N Matsumine H Yamamura Y Minoshima S Yokochi M Mizuno Y Shimizu N Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature. 1998; 392: 605-608Crossref PubMed Scopus (3891) Google Scholar; Leroy et al. Leroy et al., 1998aLeroy E Anastasopoulos D Konitsiotis S Lavedan C Polymeropoulos MH Deletions in the parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease.Hum Genet. 1998; 103: 424-427Crossref PubMed Scopus (120) Google Scholar; Lücking et al. Lücking et al., 1998Lücking CB Abbas N Durr A Bonifati V Bonnet AM de Broucker T De Michele G Wood NW Agid Y Brice A Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group.Lancet. 1998; 352: 1355-1356Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar; Abbas et al. Abbas et al., 1999Abbas N Lücking CB Ricard S Durr A Bonifati V De Michele G Bouley S Vaughan JR Gasser T Marconi R Broussolle E Brefel-Courbon C Harhangi BS Oostra BA Fabrizio E Bohme GA Pradier L Wood NW Filla A Meco G Denefle P Agid Y Brice A A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.Hum Mol Genet. 1999; 8: 567-574Crossref PubMed Scopus (470) Google Scholar; Klein et al. Klein et al., 2000Klein C Pramstaller PP Kis B Page CC Kann M Leung J Woodward H Castellan CC Scherer M Vieregge P Breakefield XO Kramer PL Ozelius LJ Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype.Ann Neurol. 2000; 48: 65-71Crossref PubMed Scopus (190) Google Scholar; Maruyama et al. Maruyama et al., 2000Maruyama M Ikeuchi T Saito M Ishikawa A Yuasa T Tanaka H Hayashi S Wakabayashi K Takahashi H Tsuji S Novel mutations, pseudo-dominant inheritance, and possible familial effects in patients with autosomal recessive juvenile parkinsonism.Ann Neurol. 2000; 48: 245-250Crossref PubMed Scopus (85) Google Scholar; Muñoz et al. Muñoz et al., 2000Muñoz E Pastor P Marti MJ Oliva R Tolosa E A new mutation in the parkin gene in a patient with atypical autosomal recessive juvenile parkinsonism.Neurosci Lett. 2000; 289: 66-68Crossref PubMed Scopus (24) Google Scholar; Yamamura et al. Yamamura et al., 2000Yamamura Y Hattori N Matsumine H Kuzuhara S Mizuno Y Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification.Brain Dev (Suppl). 2000; 22: 87-91Abstract Full Text Full Text PDF Google Scholar). The frequency of these mutations in Europe was estimated at 50% in families with early-onset parkinsonism that could have been autosomal recessive inheritance and at 18% in patients who had isolated parkinsonism with onset at age ≤45 years (Lücking et al. Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar). Interestingly, several mutations were found repeatedly in index patients (Hattori et al. Hattori et al., 1998aHattori N Kitada T Matsumine H Asakawa S Yamamura Y Yoshino H Kobayashi T Yokochi M Wang M Yoritaka A Kondo T Kuzuhara S Nakamura S Shimizu N Mizuno Y Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals.Ann Neurol. 1998; 44: 935-941Crossref PubMed Scopus (281) Google Scholar; Lücking et al. Lücking et al., 1998Lücking CB Abbas N Durr A Bonifati V Bonnet AM de Broucker T De Michele G Wood NW Agid Y Brice A Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group.Lancet. 1998; 352: 1355-1356Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar; Abbas et al. Abbas et al., 1999Abbas N Lücking CB Ricard S Durr A Bonifati V De Michele G Bouley S Vaughan JR Gasser T Marconi R Broussolle E Brefel-Courbon C Harhangi BS Oostra BA Fabrizio E Bohme GA Pradier L Wood NW Filla A Meco G Denefle P Agid Y Brice A A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.Hum Mol Genet. 1999; 8: 567-574Crossref PubMed Scopus (470) Google Scholar). In our series of patients, the deletion of exon 3 (n=11), the Arg275Trp mutation (n=8), the c.202-203 delAG mutation (n=6), and the c.255delA mutation (n=6) were found repeatedly. They may therefore result from recurrent, de novo mutational events or from founder effects. Divergent alleles of markers closely linked to the parkin locus would suggest independent de novo mutations, whereas conservation of alleles would support the hypothesis of a founder effect. In the present study, haplotype analysis was performed with 10 microsatellite markers covering a 4.7-cM region that contains the parkin gene, which is localized on chromosome 6q25.2-q27. The subjects were members of 48 families with early-onset autosomal recessive parkinsonism who carried 14 different mutations of the parkin gene found in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas there is evidence of founder effects in some families with point mutations. Forty-eight families with early-onset parkinsonism caused by mutations in the parkin gene, including 69 patients and 49 unaffected relatives, were studied. All but four families (families TRUS and KUZ from Russia, families EGPD 25-95 and PW from Germany) have been described elsewhere (Lücking et al. Lücking et al., 1998Lücking CB Abbas N Durr A Bonifati V Bonnet AM de Broucker T De Michele G Wood NW Agid Y Brice A Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group.Lancet. 1998; 352: 1355-1356Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar; Tassin et al. Tassin et al., 1998Tassin J Durr A de Broucker T Abbas N Bonifati V De Michele G Bonnet AM Broussolle E Pollak P Vidailhet M De Mari M Marconi R Medjbeur S Filla A Meco G Agid Y Brice A Chromosome 6-linked autosomal recessive early-onset Parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. The French Parkinson's Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson's Disease.Am J Hum Genet. 1998; 63: 88-94Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar; Abbas et al. Abbas et al., 1999Abbas N Lücking CB Ricard S Durr A Bonifati V De Michele G Bouley S Vaughan JR Gasser T Marconi R Broussolle E Brefel-Courbon C Harhangi BS Oostra BA Fabrizio E Bohme GA Pradier L Wood NW Filla A Meco G Denefle P Agid Y Brice A A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.Hum Mol Genet. 1999; 8: 567-574Crossref PubMed Scopus (470) Google Scholar). The families were selected for parkin analysis according to the following criteria: (1) symptoms of parkinsonism (akinesia, rigidity, or tremor), (2) marked improvement resulting from levodopa treatment, (3) age at onset ≤45 years for at least one affected sib, and (4) family history compatible with autosomal recessive inheritance (except family PW). In 13 of the 48 families, only one member was affected (referred to as isolated cases). These individuals were selected according to the same clinical criteria but had no family history of parkinsonism. They carried parkin gene mutations, on one or both alleles, that were detected at least twice in unrelated index patients (fig. 1B). The numbers and origins of the patients are summarized in table 1.Table 1Number and Origin of Index Patients with parkin Mutations Detected More than OnceNo. of Index PatientsbBecause index patients were counted separately for the various repeated mutations, the total number (n=60) is greater than the number of families studied (n=48).MutationaDel = deletion; Dup = duplication.FamilialIsolatedNo. of HaplotypesCountry of OrigincAl = Algeria; Ar = Argentina; F = France; G = Germany; Ir = Ireland; It = Italy; L = Lebanon; N = The Netherlands; Pa = Pakistan; Po = Portugal; R = Russia; UK = United Kingdom; V = Vietnam.(No.)Del2403It (3), F (1)Del3928F (3), N(3), UK (1), It (2), Po (1), R (1)Del3-4312It (2), F (1), G (1)Del4404F (1), It (1), UK (1), G (1)Del5303F (1), It (1), V (1)Del5-6032L (1), Pa (1), UK (1)Dup3212It (1), Al (1), S (1)Dup7201Ar (1), N (1)Lys211Asn202N (2)c.321-322insGT201F (1), G (1)Gly430Asp111UK (1), Ir (1)c.255delA425F (4), S (1), Po (1)Arg275Trp446F (2), It (2), Ir (1), UK (1), G (1), G/Ir (1)c.202-203delAG334UK (2), F (1), N (1), It (1), R (1)a Del = deletion; Dup = duplication.b Because index patients were counted separately for the various repeated mutations, the total number (n=60) is greater than the number of families studied (n=48).c Al = Algeria; Ar = Argentina; F = France; G = Germany; Ir = Ireland; It = Italy; L = Lebanon; N = The Netherlands; Pa = Pakistan; Po = Portugal; R = Russia; UK = United Kingdom; V = Vietnam. Open table in a new tab Blood samples were taken, after written informed consent was obtained, from 69 patients and 49 unaffected relatives, and genomic DNA was extracted using standard procedures. Genotyping was performed by PCR, using the primers specified in the Genome Database (GDB), with the following microsatellite DNA markers: D6S1581 (1 cM), D6S959 (0.2 cM), D6S1579 (0.3 cM), D6S305 (0.1 cM), AFMa155td9 (0 cM), AFMb281wf1 (0.1 cM), D6S411 (0 cM), D6S1550 (1.9 cM), D6S1035 (1.1 cM), and D6S1599 (fig. 1A) (genetic distances according to the Whitehead Institute for Biomedical Research). The physical positions of markers D6S411, AFMa155td9, AFMb281wf1, D6S1550, and D6S1599 differ partly from the genetic map and were determined with the use of clones from the Sanger Center (PAC 292F10 and RP1-45F6). Marker D6S305 was positioned, on the basis of PCR results, in patients with various exon deletions (Leroy et al. Leroy et al., 1998bLeroy E Boyer R Auburger G Leube B Ulm G Mezey E Harta G Brownstein MJ Jonnalagada S Chernova T Dehejia A Lavedan C Gasser T Steinbach PJ Wilkinson KD Polymeropoulos MH The ubiquitin pathway in Parkinson's disease.Nature. 1998; 395: 451-452Crossref PubMed Scopus (1330) Google Scholar; Lücking et al. Lücking et al., 2000Lücking CB Durr A Bonifati V Vaughan J De Michele G Gasser T Harhangi BS Meco G Denefle P Wood NW Agid Y Brice A Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group.N Engl J Med. 2000; 342: 1560-1567Crossref PubMed Scopus (1178) Google Scholar). Marker D6S1599 was amplified with the following primers: D6S1599 forward, 5′-GGG TGT GCT TGG ATT CCT TCA TG-3′, and D6S1599 reverse, 5′-TAG CAT GTG GAC TGC ATA TCA AC-3′. The primers were labeled by fluorescence, and PCR products were analyzed on an ABI 377 automated sequencer with the GENESCAN 3.1 and GENOTYPER 1.1.1 software programs (all from Applied Biosystems). To ensure accurate sizing of the alleles, a control DNA sample of individual 1347.02, from the Centre d’Etude du Polymorphisme Humain, was tested for each marker, and allele numbers were assigned in increasing order from the smallest to the largest PCR product. Haplotypes were constructed manually to include a minimum number of recombinations. For each mutation, the disease-associated haplotypes (DHs) were compared among families, to detect (1) common parkin haplotypes that would indicate that the families were related and (2) a common ancestral DH. The haplotypes constructed in families with known consanguinity were considered as a single haplotype for statistical analysis. The difference in allele distribution between normal and carrier chromosomes was evaluated by χ2 and two-tailed Fisher's exact tests, with Yates correction when appropriate. The most frequent allele on disease-bearing chromosomes was defined as a single allele, and the others were pooled to form a second allele. The presence of linkage disequilibrium was tested by D = χ2 / N , where N is the total number of DHs and control chromosomes used. A P value <.01 was considered to be statistically significant. The proportion of carrier chromosomes bearing the original associated allele was calculated with the equation δ=(PD-PN)/(1-PN), where PD and PN are the frequencies of carrier and normal chromosomes, respectively. The control population comprised 140 chromosomes from normal, white subjects. The origins of the 69 patients and 49 relatives from 48 families with early-onset parkinsonism are shown in table 1. DHs were constructed in the 38 families in which unaffected relatives were available (Table 2, Table 3, Table 4).Table 2Genotypes and Haplotypes of Index Patients with an Exon 2 Deletion in the parkin GeneIT31 (F)IT22 (F)F155 (F)IT67 (F)OriginItalyItalyFranceItalyConsanguinityNoNoNoNoMutationsdel2/del2-4del2/del3del2/del3del2/NDMarker: D6S1581718377[37] D6S95911221222 D6S157925725522 D6S1599del/deldel/1del/12[313] D6S305713197[13] D6S41134334333 AFMa155td9131122[12] AFMb281wf133323333 D6S1550234144[23] D6S1035265443[45]Note.—Reconstructed disease haplotypes bearing the analyzed mutation are underlined. The marker closest to the mutation is also underlined. When phase transmission was unknown, genotypes of the index patients are indicated in brackets. The haplotypes reconstructed in families with known consanguinity were considered as a single haplotype for statistical analysis. del = deletion; dup = duplication; F = familial parkinsonism; I = isolated parkinsonism; ND = not determined. Open table in a new tab Table 3Genotypes and Haplotypes of Index Patients with an Exon 3 Deletion in the parkin GeneF141 (F)F155 (F)F431 (F)F192 (F)F195 (F)UK57 (F)F711 (F)IT22 (F)KUS (F)JMP10 (I)UK10551 (I)OriginFranceFranceFranceNNNPortugalItalyRussiaItalyUKConsanguinityYesNoNoNoNoNoYesNoNoNoNoMutationsDel3/ Del3Del3/ Del2Del3/ NDDel3/ Dup7Del3/ Lys211AsnDel3/ Del4Del3/ Del3Del3/ Del2Del3 /Del7Del3/ Del2-3Del3/ Gly430AspMarker: D6S15813477371883777738[78][17]33 D6S9591221222235221122[12][25][23] D6S15792255225222222227[25][26][25] D6S15992212/del32233232221/del[412]13/del22 D6S30518791476733733133311[37] D6S411333435333433333333[25]33 AFMa155td9112222222212221111[12][12] AFMb281wf122333333232333233333[23] D6S15502244242222122214[24][34]22 D6S10353334356444524445[35][35][24]Note.—Data are as defined in Note to table 2. N = The Netherlands; UK = United Kingdom. Open table in a new tab Table 4Genotypes and Haplotypes of Index Patients with an Exon 4 Deletion in the parkin GeneF29 (F)DE25 (F)UK57 (F)IT05 (F)OriginFranceGermanyUnited KingdomItalyConsanguinityNoNoNoNoMutationsdel4/NDdel4/NDdel4/del3del4/del4Marker: D6S158133847793 D6S95925612251 D6S157923232225 D6S1599103412333 D6S30535337311 D6S41133333344 AFMa155td921222132 AFMb281wf133333213 D6S155024232122 D6S103525332562Note.—Data are as defined in Note to table 2. Open table in a new tab Note.— Reconstructed disease haplotypes bearing the analyzed mutation are underlined. The marker closest to the mutation is also underlined. When phase transmission was unknown, genotypes of the index patients are indicated in brackets. The haplotypes reconstructed in families with known consanguinity were considered as a single haplotype for statistical analysis. del = deletion; dup = duplication; F = familial parkinsonism; I = isolated parkinsonism; ND = not determined. Note.— Data are as defined in Note to table 2. N = The Netherlands; UK = United Kingdom. Note.— Data are as defined in Note to table 2. Genotypes or haplotypes of patients with deletion of exon 2, 3, or 4 are shown in tables 2, 3, and 4, respectively. Patients with exon 2 deletions did not share common haplotypes, and alleles at markers D6S1579 and D6S305, which flank the deletion, also differed (table 2). Although allele 3 at marker AFMb281wf1 was present on 100% of the disease-causing chromosomes, the association was not statistically significant, because this allele was present in 80% of the control population. Interestingly, marker D6S1599, located in intron 2, was deleted with exon 2 in 3 of 4 families (table 2). This observation indicated the existence of at least two distinct breakpoints and supported the hypothesis of independent mutational events. Haplotypes of the two patients with deletions of exons 3 and 4, only one of which was associated with a deletion of marker D6S1599, also differed (data not shown). Four of the five haplotypes that segregated with exon 4 deletions were identical at markers AFMa155td9, AFMb281wf1, and D6S1550 (table 4). However, the association was not statistically significant, because these were the most frequent alleles in the control population (50%, 82%, and 46%, respectively). Furthermore, the haplotypes for the markers closest to the deletion (D6S1599 and D6S305) differed, suggesting independent recurrent mutations (table 4). However patient IT05, who was homozygous for an exon 4 deletion and who had no known consanguinity, was homozygous for markers D6S1599, D6S305, and D6S411, which flank the deletion. Although the patient’s parents were not known to be related, a common founder for the exon 4 deletion on both chromosomes may be suspected. Eleven index patients had exon 3 deletions, the most frequent mutation in the parkin gene, but no significant association was observed between allele markers and the DHs (table 3). Allele 2 at marker D6S1599, the marker closest to the mutation, was present on 4 of 10 disease-bearing chromosomes but was also the most frequent allele in the control population (43%). Furthermore, patients F155 and JMP10 carried alleles 12 and 13, respectively, (whose sizes were very different from" @default.
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