{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:04:42Z","timestamp":1791295482207,"version":"4.1.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,7,8]]},"abstract":"<jats:p>Friedreich\u2019s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for \u224817% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through \u201cpremutation\u201d intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.<\/jats:p>","DOI":"10.1073\/pnas.94.14.7452","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:31:44Z","timestamp":1027679504000},"page":"7452-7457","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":277,"title":["Evolution of the Friedreich\u2019s ataxia trinucleotide repeat expansion: Founder effect and\u2009premutations"],"prefix":"10.1073","volume":"94","author":[{"given":"Mireille","family":"Coss\u00e9e","sequence":"first","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mich\u00e8le","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Campuzano","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Reutenauer","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Moutou","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Mandel","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Koenig","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale\/Centre National de la Recherche Scientifique\/Universit\u00e9 Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France; and Institut de Chimie Biologique, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Humaine, Facult\u00e9 de M\u00e9decine, 11 rue Human, 67085 Strasbourg-Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1997,7,8]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"103","volume-title":"Epidemiology of Spinocerebellar Degeneration in Western Norway: Hereditary Diseases","author":"Skre H","year":"1980","unstructured":"H Skre Epidemiology of Spinocerebellar Degeneration in Western Norway: Hereditary Diseases (Univ. of Tokyo Press, Tokyo), pp. 103 (1980)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0317167100022873"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1981.tb01052.x"},{"key":"e_1_3_3_4_2","first-page":"523","volume":"35","author":"Romeo G","year":"1983","unstructured":"G Romeo, P Menozzi, A Ferlini, S Fadda, S Di Donato, G Uziel, B Lucci Am J Hum Genet 35, 523\u2013529 (1983).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1990.tb03566.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5254.1423"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199610173351601"},{"key":"e_1_3_3_8_2","first-page":"554","volume":"59","author":"Filla A","year":"1996","unstructured":"A Filla, G De Michele, F Cavalcanti, L Pianese, A Monticelli, G Campanella, S Cocozza Am J Hum Genet 59, 554\u2013560 (1996).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ne.19.030196.000455"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0792-257"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0593-72"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.5.1796"},{"key":"e_1_3_3_13_2","first-page":"228","volume":"47","author":"Pandolfo M","year":"1990","unstructured":"M Pandolfo, G Sirugo, A Antonelli, L Weitnauer, L Ferreti, M Leone, I Dones, A Cerino, R Fujita, A Hanauer, J-L Mandel, S Di Donato Am J Hum Genet 47, 228\u2013235 (1990).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000472400"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1159\/000472198"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.6.909"},{"key":"e_1_3_3_17_2","first-page":"1061","volume":"57","author":"Montermini L","year":"1995","unstructured":"L Montermini, F Rodius, L Pianese, M D Molt\u00f3, M Coss\u00e9e, V Campuzano, F Cavalcanti, A Monticelli, F Palau, G Gyapay, M Wenhert, F Zara, P I Patel, S Cocozza, M Koenig, M Pandolfo Am J Hum Genet 57, 1061\u20131067 (1995).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_18_2","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook J","year":"1989","unstructured":"J Sambrook, E F Fritsch, T Maniatis Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. 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