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

Autor: Loureiro JR; 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, Portugal., Oliveira CL; 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., Mota C; 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., Castro AF; 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., Costa C; Department of Neurology, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal., Loureiro JL; 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, Portugal., Coutinho P; 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., Martins S; 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, Portugal., Sequeiros J; 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, Portugal., Silveira I; 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.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2019 Apr; Vol. 40 (4), pp. 404-412. Date of Electronic Publication: 2019 Jan 09.
DOI: 10.1002/humu.23704
Abstrakt: 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.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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