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Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

2018; Wiley; Volume: 40; Issue: 4 Linguagem: Inglês

10.1002/humu.23704

1098-1004

Joana R. Loureiro, Cláudia Oliveira, Carolina Pimenta Mota, Ana F. Castro, Cristina Costa, José L. Loureiro, Paula Coutinho, Sandra Martins, Jorge Sequeiros, Isabel Silveira,

Genetics and Neurodevelopmental Disorders

Human MutationVolume 40, Issue 4 p. 404-412 RESEARCH ARTICLE Mutational mechanism for DAB1 (ATTTC)n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution Joana R. Loureiro, Joana R. Loureiro Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal ICBAS, Universidade do Porto, Porto, PortugalSearch for more papers by this authorCláudia L. Oliveira, Cláudia L. Oliveira Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, PortugalSearch for more papers by this authorCarolina Mota, Carolina Mota Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, PortugalSearch for more papers by this authorAna F. Castro, Ana F. Castro Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, PortugalSearch for more papers by this authorCristina Costa, Cristina Costa Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, Amadora, PortugalSearch for more papers by this authorJosé L. Loureiro, José L. Loureiro IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Department of Neurology, Hospital São Sebastião, Feira, PortugalSearch for more papers by this authorPaula Coutinho, Paula Coutinho IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, PortugalSearch for more papers by this authorSandra Martins, Sandra Martins Population Genetics & Evolution, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalSearch for more papers by this authorJorge Sequeiros, Jorge Sequeiros IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal ICBAS, Universidade do Porto, Porto, Portugal UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, PortugalSearch for more papers by this authorIsabel Silveira, Corresponding Author Isabel Silveira isilveir@ibmc.up.pt orcid.org/0000-0002-2610-5260 Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal Correspondence Isabel Silveira, PhD, Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde and IBMC – Institute for Molecular and Cell Biology, Universidade do Porto, Portugal, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal Email: isilveir@ibmc.up.ptSearch for more papers by this author Joana R. Loureiro, Joana R. Loureiro Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal ICBAS, Universidade do Porto, Porto, PortugalSearch for more papers by this authorCláudia L. Oliveira, Cláudia L. Oliveira Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, PortugalSearch for more papers by this authorCarolina Mota, Carolina Mota Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, PortugalSearch for more papers by this authorAna F. Castro, Ana F. Castro Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, PortugalSearch for more papers by this authorCristina Costa, Cristina Costa Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, Amadora, PortugalSearch for more papers by this authorJosé L. Loureiro, José L. Loureiro IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Department of Neurology, Hospital São Sebastião, Feira, PortugalSearch for more papers by this authorPaula Coutinho, Paula Coutinho IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, PortugalSearch for more papers by this authorSandra Martins, Sandra Martins Population Genetics & Evolution, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, PortugalSearch for more papers by this authorJorge Sequeiros, Jorge Sequeiros IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal ICBAS, Universidade do Porto, Porto, Portugal UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, PortugalSearch for more papers by this authorIsabel Silveira, Corresponding Author Isabel Silveira isilveir@ibmc.up.pt orcid.org/0000-0002-2610-5260 Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal IBMC- Institute for Molecular and Cell Biology, Universidade do Porto, Porto, Portugal Correspondence Isabel Silveira, PhD, Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde and IBMC – Institute for Molecular and Cell Biology, Universidade do Porto, Portugal, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal Email: isilveir@ibmc.up.ptSearch for more papers by this author First published: 26 December 2018 https://doi.org/10.1002/humu.23704Citations: 12 Communicated by George P. Patrinos Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n. Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process. Citing Literature Supporting Information Filename Description humu23704-sup-0001-SuppMat.pdf103.4 KB Supplemental Table S1. PCR conditions and primers for selected SNPs. Supplemental Table S2. Haplotypes in pure and interrupted non-pathogenic alleles. Supplemental Table S3. Haplotypes sharing the 5 rare SNP alleles from haplotype VIII (SCA37 haplotype) available in 1000 g phase 3. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume40, Issue4April 2019Pages 404-412 RelatedInformation