Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37

Spinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) g...

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Detalles Bibliográficos
Autores: Sanchez Flores, Marina, Corral Juan, Marc, Gasch Navalón, Esther, Cirillo, Davide|||0000-0003-4982-4716, Sanchez, Ivelisse, Matilla Dueñas, Antoni
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/403879
Acceso en línea:https://hdl.handle.net/2117/403879
https://dx.doi.org/10.1007/s00439-024-02644-7
Access Level:acceso abierto
Palabra clave:Genomics
Nanopores
Spinocerebellar ataxia type 37
Rare disease
Neurodegenerative disorders
Simulació per ordinador
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
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oai_identifier_str oai:upcommons.upc.edu:2117/403879
network_acronym_str ES
network_name_str España
repository_id_str
spelling Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37Sanchez Flores, MarinaCorral Juan, MarcGasch Navalón, EstherCirillo, Davide|||0000-0003-4982-4716Sanchez, IvelisseMatilla Dueñas, AntoniGenomicsNanoporesSpinocerebellar ataxia type 37Rare diseaseNeurodegenerative disordersSimulació per ordinadorÀrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::BioinformàticaSpinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) gene leading to cerebellar dysregulation. Herein, we determine the precise configuration of the pathogenic 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n SCA37 alleles by CRISPR–Cas9 and long-read nanopore sequencing, reveal their epigenomic signatures in SCA37 lymphocytes, fibroblasts, and cerebellar samples, and establish new molecular and clinical correlations. The 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n pathogenic allele configurations revealed repeat instability and differential methylation signatures. Disease age of onset negatively correlated with the (ATTTC)n, and positively correlated with the 3ʹ(ATTTT)n. Geographic origin and gender significantly correlated with age of onset. Furthermore, significant predictive regression models were obtained by machine learning for age of onset and disease evolution by considering gender, the (ATTTC)n, the 3ʹ(ATTTT)n, and seven CpG positions differentially methylated in SCA37 cerebellum. A common 964-kb genomic region spanning the (ATTTC)n insertion was identified in all SCA37 patients analysed from Portugal and Spain, evidencing a common origin of the SCA37 mutation in the Iberian Peninsula originating 859 years ago (95% CI 647–1378). In conclusion, we demonstrate an accurate determination of the size and configuration of the regulatory 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n repeat tract, avoiding PCR bias amplification using CRISPR/Cas9-enrichment and nanopore long-read sequencing, resulting relevant for accurate genetic diagnosis of SCA37. Moreover, we determine novel significant genotype–phenotype correlations in SCA37 and identify differential cerebellar allele-specific methylation signatures that may underlie DAB1 pathogenic dysregulation.This work was funded by the National Institute of Health Carlos III (ISCIII)(PI17/00534).Peer ReviewedSpringer20242024-01-0120242024-03-06journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/403879https://dx.doi.org/10.1007/s00439-024-02644-7reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/4038792026-05-27T15:37:01Z
dc.title.none.fl_str_mv Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
title Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
spellingShingle Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
Sanchez Flores, Marina
Genomics
Nanopores
Spinocerebellar ataxia type 37
Rare disease
Neurodegenerative disorders
Simulació per ordinador
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
title_short Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
title_full Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
title_fullStr Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
title_full_unstemmed Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
title_sort Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37
dc.creator.none.fl_str_mv Sanchez Flores, Marina
Corral Juan, Marc
Gasch Navalón, Esther
Cirillo, Davide|||0000-0003-4982-4716
Sanchez, Ivelisse
Matilla Dueñas, Antoni
author Sanchez Flores, Marina
author_facet Sanchez Flores, Marina
Corral Juan, Marc
Gasch Navalón, Esther
Cirillo, Davide|||0000-0003-4982-4716
Sanchez, Ivelisse
Matilla Dueñas, Antoni
author_role author
author2 Corral Juan, Marc
Gasch Navalón, Esther
Cirillo, Davide|||0000-0003-4982-4716
Sanchez, Ivelisse
Matilla Dueñas, Antoni
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Genomics
Nanopores
Spinocerebellar ataxia type 37
Rare disease
Neurodegenerative disorders
Simulació per ordinador
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
topic Genomics
Nanopores
Spinocerebellar ataxia type 37
Rare disease
Neurodegenerative disorders
Simulació per ordinador
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
description Spinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) gene leading to cerebellar dysregulation. Herein, we determine the precise configuration of the pathogenic 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n SCA37 alleles by CRISPR–Cas9 and long-read nanopore sequencing, reveal their epigenomic signatures in SCA37 lymphocytes, fibroblasts, and cerebellar samples, and establish new molecular and clinical correlations. The 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n pathogenic allele configurations revealed repeat instability and differential methylation signatures. Disease age of onset negatively correlated with the (ATTTC)n, and positively correlated with the 3ʹ(ATTTT)n. Geographic origin and gender significantly correlated with age of onset. Furthermore, significant predictive regression models were obtained by machine learning for age of onset and disease evolution by considering gender, the (ATTTC)n, the 3ʹ(ATTTT)n, and seven CpG positions differentially methylated in SCA37 cerebellum. A common 964-kb genomic region spanning the (ATTTC)n insertion was identified in all SCA37 patients analysed from Portugal and Spain, evidencing a common origin of the SCA37 mutation in the Iberian Peninsula originating 859 years ago (95% CI 647–1378). In conclusion, we demonstrate an accurate determination of the size and configuration of the regulatory 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n repeat tract, avoiding PCR bias amplification using CRISPR/Cas9-enrichment and nanopore long-read sequencing, resulting relevant for accurate genetic diagnosis of SCA37. Moreover, we determine novel significant genotype–phenotype correlations in SCA37 and identify differential cerebellar allele-specific methylation signatures that may underlie DAB1 pathogenic dysregulation.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-01-01
2024
2024-03-06
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/403879
https://dx.doi.org/10.1007/s00439-024-02644-7
url https://hdl.handle.net/2117/403879
https://dx.doi.org/10.1007/s00439-024-02644-7
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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