text: AJHG - 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
  Article InformationPDF (126 kb)Full Text with Thumbnail FiguresFull Text with Large FiguresExport CitationCited by in Scopus (55)Request permissionPubMedArticles by Johann TassinArticles by Alexis BriceRelated ArticlesAutosomal Recessive Juvenile Parkinsonism Maps to 6q25.2-q27...Autosomal Recessive Juvenile Parkinsonism Maps to 6q25.2-q27 in Four Ethnic Groups: Detailed Genetic Mapping of the Linked RegionThe American Journal of Human Genetics, Volume 63, Issue 1, 1 July 1998, Pages 80-87Alison C. Jones, Yasuhiro Yamamura, Laura Almasy, Saeed Bohlega, Bülent Elibol, Jean Hubble, Shigeki Kuzuhara, Masao Uchida, Tsutomu Yanagi, Daniel E. Weeks and Torbjoern G. NygaardAbstractSummaryParkinson disease (PD) is a common neurodegenerative condition associated with degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. There is increasing evidence that genetic factors play a role in the etiology of PD, although genetic heterogeneity is likely. An autosomal dominant syndrome with many similarities to sporadic PD has been mapped to 4q21-22 in a large Italian pedigree and has been found to be due to mutation of the alpha-synuclein gene. However, this gene appears to account for only a minority of PD, and a susceptibility locus for autosomal dominant parkinsonism has recently been mapped, on 2p13. Autosomal recessive juvenile parkinsonism (JP), which shows marked clinical similarity to PD, maps to 6q25.2-q27. We found linkage to this region in a group of 15 families from four distinct ethnic backgrounds. A full genomic screen excluded other candidate regions. We have constructed a detailed genetic map of the linked region and have mapped the position of the manganese superoxide dismutase gene (SOD2). Recombination events restricted the JP locus to a 6.9-cM region and excluded SOD2. The apparent homozygosity for null alleles at D6S955 in one family suggested a deletion and finer localization of the JP locus.Abstract | Full Text | PDF (142 kb)Origin of the Mutations in the parkin Gene in Europe: Exon R...Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder EffectsThe American Journal of Human Genetics, Volume 68, Issue 3, 1 March 2001, Pages 617-626Magali Periquet, Christoph B. Lücking, Jenny R. Vaughan, Vincenzo Bonifati, Alexandra Dürr, Giuseppe De Michele, Martin W. Horstink, Matt Farrer, Sergei N. Illarioshkin, Pierre Pollak, Michel Borg, Christine Brefel-Courbon, Patrice Denefle, Giuseppe Meco, Thomas Gasser, Monique M.B. Breteler, Nick W. Wood, Yves Agid, Alexis Brice, the French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease AbstractA 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.Abstract | Full Text | PDF (254 kb)A Simple Method for Analyzing Microsatellite Allele Image Pa...A Simple Method for Analyzing Microsatellite Allele Image Patterns Generated from DNA Pools and Its Application to Allelic Association StudiesThe American Journal of Human Genetics, Volume 62, Issue 5, 1 May 1998, Pages 1189-1197Johanna Daniels, Peter Holmans, Nigel Williams, Dragana Turic, Peter McGuffin, Robert Plomin and Michael J. OwenAbstractSummaryAllelic association studies provide the most powerful method for locating genes of small effect contributing to complex diseases and traits. However, in outbred populations, allelic association is usually maintained only over distances of ≤1 cM. Therefore, systematic searches over large regions are costly. Here we present a method involving DNA pooling that can be used as a rapid preliminary screen for allelic association with the most common class of polymorphic markers, single-sequence repeats. Patient and control samples are pooled separately, and markers are typed in the two pools. By use of primers with fluorescent 5′ ends, PCR products can be analyzed on an automated sequencing apparatus. Allele image patterns (AIPs) produced for the two groups are overlaid and differences in pattern area between pools computed. From this, a ΔAIP statistic is calculated from the difference in areas between the two AIPs expressed as a fraction of the total shared and nonshared area. AIPs of a range of different-sized pools were generated by computer simulation for markers with a range of allele sizes and frequencies. ΔAIPs from pools and χ2 values for individual genotypings were compared, with both simulated and real data from microsatellite markers. The results demonstrated a high correlation between ΔAIP and χ2 values. ΔAIP analysis of real microsatellite data indicated the feasibility of using this method in systematic searches for allelic association and generated a small number of false positives but few false negatives. We conclude that ΔAIP analysis of DNA pools can be used effectively and efficiently as a rapid screen for allelic association in case-control studies.Abstract | Full Text | PDF (602 kb)…moreGet BookmarkAdd BookmarkDeliciousDiggRedditFacebookStumbleUponCopyright © 1998 The American Society of Human Genetics All rights reserved.The American Journal of Human Genetics, Volume 63, Issue 1, 88-94, 1 July 1998doi:10.1086/301934Previous ArticleTable of ContentsNext ArticleChromosome 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
  Johann Tassin1, *, Alexandra Dürr1, *, Thomas de Broucker2, Nacer Abbas1, Vincenzo Bonifati3, Giuseppe De Michele4, Anne-Marie Bonnet1, Emmanuel Broussolle5, Pierre Pollak6, Marie Vidailhet1, Michele De Mari7, Roberto Marconi8, Soraya Medjbeur1, Allessandro Filla4, Giuseppe Meco3, Yves Agid1, Alexis Brice1, , and The French Parkinson's Disease Genetics Study Group, and The European Consortium on Genetic Susceptibility in Parkinson's Disease1 INSERM U289, Hôpital de la Salpêtrière, Paris;2 Service de Neurologie, Hôpital Casanova, Saint Denis, France;3 Dipartimento di Scienze Neurologiche, Università "La Sapienza," Rome;4 Dipartimento di Scienze Neurologiche, Università Federico II, Naples;5 Hôpital Neurologique, Lyon;6 Centre Hospitalier Régional, Grenoble, France;7 Institute of Neurology, University of Bari, Bari, Italy; and8 Divisione di Neurologia, Ospedale Misericordia, Grosseto, ItalyAddress for correspondence and reprints: Prof. Alexis Brice, INSERM U289, Hôpital de la Salpêtrière, 47 bd de l'Hôpital, 75651 Paris Cedex 13, France * These authors contributed equally to this work.AbstractThe gene for autosomal recessive juvenile Parkinsonism (AR-JP) recently has been mapped to chromosome 6q25.2–27 in Japanese families. We have tested one Algerian and 10 European multiplex families with early-onset Parkinson disease for linkage to this locus, with marker D6S305. Homogeneity analysis provided a conditional probability in favor of linkage of >.9 in eight families, which were analyzed further with eight microsatellite markers spanning the 17-cM AR-JP region. Haplotype reconstruction for eight families and determination of the smallest region of homozygosity in two consanguineous families reduced the candidate interval to 11.3 cM. If the deletion of two microsatellite markers (D6S411 and D6S1550) that colocalize on the genetic map and that segregate with the disease in the Algerian family is taken into account, the candidate region would be reduced to <1 cM. These findings should facilitate identification of the corresponding gene. We have confirmed linkage of AR-JP, in European families and in an Algerian family, to the PARK2 locus. PARK2 appears to be an important locus for AR-JP in European patients. The clinical spectrum of the disease in our families, with age at onset ≤58 years and the presence of painful dystonia in some patients, is broader than that reported previously.	Visit another Cell Press journal