caa a22 4500 397575076 CHVBK 20180308164853.0 cr unu---uuuuu 161202e199607 xx s 000 0 eng 10.1093/hmg/5.7.923 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.7.923 Intergenerational Instability of the CAG Repeat of the Gene for Machado-Joseph Disease (MJD1) is Affected by the Genotype of the Normal Chromosome: Implications for the Molecular Mechanisms of the Instability of the CAG Repeat [Elektronische Daten] [S. Igarashi, Y. Takiyama, G. Cancel, E. A. Rogaeva, H. Sasaki, A. Wakisaka, Y.-X. Zhou, H. Takano, K. Endo, K. Sanpei, M. Oyake, H. Tanaka, G. Stevanin, N. Abbas, A. Dürr, E. I. Rogaev, R. Sherrington, T. Tsuda, M. Ikeda, E. Cassa, M. Nishizawa, A. Benomar, J. Julien, J. Weissenbach, G.-X. Wang, Y. Agid, P. H. St. George-Hyslop, A. Brice, S. Tsuji] Machado-Joseph disease (MJD) is an autosomal dominant multisystem neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q432.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3′ end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (←2 or >2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter-allelic interaction is involved in the intergenerational instability of the expanded CAG repeat. © 1996 Oxford University Press Igarashi S. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Takiyama Y. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Cancel G. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut Rogaeva E. A. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut Sasaki H. Department of Neurology, Hokkaido University School of Medicine, Sapporo 060, Japan aut Wakisaka A. Department of Pathology, Hokkaido University School of Medicine, Sapporo 060, Japan aut Zhou Y.-X Department of Neurology, China-Japan Friendship Hospital, Hepingli, Beijing, 100029, China aut Takano H. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Endo K. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Sanpei K. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Oyake M. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Tanaka H. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Stevanin G. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut Abbas N. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut Dürr A. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut Rogaev E. I. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut Sherrington R. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut Tsuda T. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut Ikeda M. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut Cassa E. Departament de Neurologia, Hospital das Clinicas, Universidade de Sao Paulo, Sao Paulo, Brazil aut Nishizawa M. Department of Neurology, Jichi Medical School, Minamikawachi, Tochigi 32904, Japan aut Benomar A. Service de Neurologie de l'Hopital des Spécialités, Rabat, Morocco aut Julien J. Service de Neurologie, CHU de Bordeaux, Pessac, France aut Weissenbach J. Généthon, 1 rue de l'Internationale, 91000 Evry, and Unité de Genetique Moleculaire Human, CNRS URA 1445, Institut Pasteur, 75724 Paris Cedex, France aut Wang G.-X Department of Neurology, China-Japan Friendship Hospital, Hepingli, Beijing, 100029, China aut Agid Y. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut St. George-Hyslop P. H. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut Brice A. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut Tsuji S. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut Human Molecular Genetics Oxford University Press 5/7(1996-07), 923-932 0964-6906 5:7<923 1996 5 hmg https://doi.org/10.1093/hmg/5.7.923 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.7.923 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Igarashi S. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Takiyama Y. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Cancel G. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut NATIONALLICENCE 700 1- Rogaeva E. A. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut NATIONALLICENCE 700 1- Sasaki H. Department of Neurology, Hokkaido University School of Medicine, Sapporo 060, Japan aut NATIONALLICENCE 700 1- Wakisaka A. Department of Pathology, Hokkaido University School of Medicine, Sapporo 060, Japan aut NATIONALLICENCE 700 1- Zhou Y.-X Department of Neurology, China-Japan Friendship Hospital, Hepingli, Beijing, 100029, China aut NATIONALLICENCE 700 1- Takano H. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Endo K. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Sanpei K. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Oyake M. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Tanaka H. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 700 1- Stevanin G. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut NATIONALLICENCE 700 1- Abbas N. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut NATIONALLICENCE 700 1- Dürr A. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut NATIONALLICENCE 700 1- Rogaev E. I. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut NATIONALLICENCE 700 1- Sherrington R. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut NATIONALLICENCE 700 1- Tsuda T. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut NATIONALLICENCE 700 1- Ikeda M. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut NATIONALLICENCE 700 1- Cassa E. Departament de Neurologia, Hospital das Clinicas, Universidade de Sao Paulo, Sao Paulo, Brazil aut NATIONALLICENCE 700 1- Nishizawa M. Department of Neurology, Jichi Medical School, Minamikawachi, Tochigi 32904, Japan aut NATIONALLICENCE 700 1- Benomar A. Service de Neurologie de l'Hopital des Spécialités, Rabat, Morocco aut NATIONALLICENCE 700 1- Julien J. Service de Neurologie, CHU de Bordeaux, Pessac, France aut NATIONALLICENCE 700 1- Weissenbach J. Généthon, 1 rue de l'Internationale, 91000 Evry, and Unité de Genetique Moleculaire Human, CNRS URA 1445, Institut Pasteur, 75724 Paris Cedex, France aut NATIONALLICENCE 700 1- Wang G.-X Department of Neurology, China-Japan Friendship Hospital, Hepingli, Beijing, 100029, China aut NATIONALLICENCE 700 1- Agid Y. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut NATIONALLICENCE 700 1- St. George-Hyslop P. H. Center for Research in Neurodegenerative Disease, University of Toronto and Department of Medicine, Division of Neurology, The Toronto Hospital, 6 Queen's Park Crescent, Toronto, Ontario, Canada, M5S 1A8 aut NATIONALLICENCE 700 1- Brice A. INSERM Unité 289, and Federation de Neurologie, Hopital de la Salpêtrière, Paris, France aut NATIONALLICENCE 700 1- Tsuji S. Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951, Japan aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/7(1996-07), 923-932 0964-6906 5:7<923 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford