Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10216/114492 |
Resumo: | Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is due to the expansion over 200 CGGs and methylation of this polymorphic region, in the 5'-UTR (untranslated region) of FMR1 (Xq27.3). We have identified four FXS mosaic males: M1-(CGG)35/(CGG)>200; M2-(CGG)26/(CGG)>200; M3-(CGG)39/(CGG)>200; and M4-(CGG)18/(CGG)125/(CGG)>200. After genotyping their respective mothers, we suggested that normal alleles of these patients resulted from post-zygotic contractions of full expansions. The detection of these four rare independent cases led us to hypothesize the existence of a large-contraction predisposing haplotype in our population. Next, we questioned whether other normal pure CGGs would have arisen through similar contractions from fully expanded alleles. To address these questions, we identified stable single-nucleotide polymorphism (SNP) lineages and related short tandem repeat (STR) haplotypes (DXS998-DXS548-FRAXAC1-FRAXAC2) of the four mosaics, 123 unrelated FXS patients and 212 controls. An extended flanking haplotype (34-44-38-336) shared by mosaics from lineage A suggested a risk lineage-specific haplotype more prone to large contractions. Other normal pure FMR1 alleles from this SNP background also shared phylogenetically close STR haplotypes, although a single (CGG)exp>(CGG)24 contraction or the loss of AGG interruptions may explain their origin. In both scenarios, multistep FMR1 mutations involving the gain or loss of several CGGs seem to underlie the evolution of the repeat. |
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Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?ChildChild, PreschoolFragile X Mental Retardation Protein/geneticsFragile X Syndrome/geneticsGene FrequencyHaplotypes/geneticsHumansMaleMicrosatellite Repeats/geneticsMiddle AgedPolymorphism, Single Nucleotide/geneticsTrinucleotide Repeats/geneticsFragile X syndrome (FXS), the most common cause of inherited intellectual disability, is due to the expansion over 200 CGGs and methylation of this polymorphic region, in the 5'-UTR (untranslated region) of FMR1 (Xq27.3). We have identified four FXS mosaic males: M1-(CGG)35/(CGG)>200; M2-(CGG)26/(CGG)>200; M3-(CGG)39/(CGG)>200; and M4-(CGG)18/(CGG)125/(CGG)>200. After genotyping their respective mothers, we suggested that normal alleles of these patients resulted from post-zygotic contractions of full expansions. The detection of these four rare independent cases led us to hypothesize the existence of a large-contraction predisposing haplotype in our population. Next, we questioned whether other normal pure CGGs would have arisen through similar contractions from fully expanded alleles. To address these questions, we identified stable single-nucleotide polymorphism (SNP) lineages and related short tandem repeat (STR) haplotypes (DXS998-DXS548-FRAXAC1-FRAXAC2) of the four mosaics, 123 unrelated FXS patients and 212 controls. An extended flanking haplotype (34-44-38-336) shared by mosaics from lineage A suggested a risk lineage-specific haplotype more prone to large contractions. Other normal pure FMR1 alleles from this SNP background also shared phylogenetically close STR haplotypes, although a single (CGG)exp>(CGG)24 contraction or the loss of AGG interruptions may explain their origin. In both scenarios, multistep FMR1 mutations involving the gain or loss of several CGGs seem to underlie the evolution of the repeat.Nature Publishing Group20172017-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10216/114492eng1434-516110.1038/jhg.2016.122Maia, NLoureiro, JROliveira, BMarques, ISantos, RJorge, PMartins, Sinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T15:21:42Zoai:repositorio-aberto.up.pt:10216/114492Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:21:40.626612Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
title |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
spellingShingle |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? Maia, N Child Child, Preschool Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics Gene Frequency Haplotypes/genetics Humans Male Microsatellite Repeats/genetics Middle Aged Polymorphism, Single Nucleotide/genetics Trinucleotide Repeats/genetics |
title_short |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
title_full |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
title_fullStr |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
title_full_unstemmed |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
title_sort |
Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? |
author |
Maia, N |
author_facet |
Maia, N Loureiro, JR Oliveira, B Marques, I Santos, R Jorge, P Martins, S |
author_role |
author |
author2 |
Loureiro, JR Oliveira, B Marques, I Santos, R Jorge, P Martins, S |
author2_role |
author author author author author author |
dc.contributor.author.fl_str_mv |
Maia, N Loureiro, JR Oliveira, B Marques, I Santos, R Jorge, P Martins, S |
dc.subject.por.fl_str_mv |
Child Child, Preschool Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics Gene Frequency Haplotypes/genetics Humans Male Microsatellite Repeats/genetics Middle Aged Polymorphism, Single Nucleotide/genetics Trinucleotide Repeats/genetics |
topic |
Child Child, Preschool Fragile X Mental Retardation Protein/genetics Fragile X Syndrome/genetics Gene Frequency Haplotypes/genetics Humans Male Microsatellite Repeats/genetics Middle Aged Polymorphism, Single Nucleotide/genetics Trinucleotide Repeats/genetics |
description |
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is due to the expansion over 200 CGGs and methylation of this polymorphic region, in the 5'-UTR (untranslated region) of FMR1 (Xq27.3). We have identified four FXS mosaic males: M1-(CGG)35/(CGG)>200; M2-(CGG)26/(CGG)>200; M3-(CGG)39/(CGG)>200; and M4-(CGG)18/(CGG)125/(CGG)>200. After genotyping their respective mothers, we suggested that normal alleles of these patients resulted from post-zygotic contractions of full expansions. The detection of these four rare independent cases led us to hypothesize the existence of a large-contraction predisposing haplotype in our population. Next, we questioned whether other normal pure CGGs would have arisen through similar contractions from fully expanded alleles. To address these questions, we identified stable single-nucleotide polymorphism (SNP) lineages and related short tandem repeat (STR) haplotypes (DXS998-DXS548-FRAXAC1-FRAXAC2) of the four mosaics, 123 unrelated FXS patients and 212 controls. An extended flanking haplotype (34-44-38-336) shared by mosaics from lineage A suggested a risk lineage-specific haplotype more prone to large contractions. Other normal pure FMR1 alleles from this SNP background also shared phylogenetically close STR haplotypes, although a single (CGG)exp>(CGG)24 contraction or the loss of AGG interruptions may explain their origin. In both scenarios, multistep FMR1 mutations involving the gain or loss of several CGGs seem to underlie the evolution of the repeat. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017 2017-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10216/114492 |
url |
http://hdl.handle.net/10216/114492 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1434-5161 10.1038/jhg.2016.122 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Nature Publishing Group |
publisher.none.fl_str_mv |
Nature Publishing Group |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799136133243731968 |