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Molecular characterization of Portuguese patients with hereditary cerebellar ataxia

Bibliographic Details
Main Author: Santos, Mariana
Publication Date: 2022
Other Authors: Damásio, Joana, Carmona, Susana, Neto, João Luís, Dehghani, Nadia, Correia Guedes, Leonor, Barbot, Clara, Barros, José, Brás, José, Sequeiros, Jorge, Guerreiro, Rita
Format: Article
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/52260
Summary: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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spelling Molecular characterization of Portuguese patients with hereditary cerebellar ataxiaCerebellar ataxiaDe novo variantExome sequencingMolecular mechanismsRecessive ataxia© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.This work was funded by National Funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04293/2020. It was also supported in part by the FCT grant FCT-ANR/BEX-GMG/0008/2013; the Porto Neurosciences and Neurologic Disease Research Initiative at the i3S (Norte-01-0145-FEDER-000008), supported by Norte Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement, also through FEDER; and by GenomePT (POCI-01-0145-FEDER-022184). M.S. was the recipient of a fellowship (SFRH/BPD/116046/2016) and acknowledges funding from FCT through program DL 57/2016—Norma Transitória.MDPIRepositório da Universidade de LisboaSantos, MarianaDamásio, JoanaCarmona, SusanaNeto, João LuísDehghani, NadiaCorreia Guedes, LeonorBarbot, ClaraBarros, JoséBrás, JoséSequeiros, JorgeGuerreiro, Rita2022-04-07T16:26:03Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/52260engCells. 2022 Mar 12;11(6):98110.3390/cells110609812073-4409info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T14:43:30Zoai:repositorio.ulisboa.pt:10451/52260Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T03:23:37.497126Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
title Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
spellingShingle Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
Santos, Mariana
Cerebellar ataxia
De novo variant
Exome sequencing
Molecular mechanisms
Recessive ataxia
title_short Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
title_full Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
title_fullStr Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
title_full_unstemmed Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
title_sort Molecular characterization of Portuguese patients with hereditary cerebellar ataxia
author Santos, Mariana
author_facet Santos, Mariana
Damásio, Joana
Carmona, Susana
Neto, João Luís
Dehghani, Nadia
Correia Guedes, Leonor
Barbot, Clara
Barros, José
Brás, José
Sequeiros, Jorge
Guerreiro, Rita
author_role author
author2 Damásio, Joana
Carmona, Susana
Neto, João Luís
Dehghani, Nadia
Correia Guedes, Leonor
Barbot, Clara
Barros, José
Brás, José
Sequeiros, Jorge
Guerreiro, Rita
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Santos, Mariana
Damásio, Joana
Carmona, Susana
Neto, João Luís
Dehghani, Nadia
Correia Guedes, Leonor
Barbot, Clara
Barros, José
Brás, José
Sequeiros, Jorge
Guerreiro, Rita
dc.subject.por.fl_str_mv Cerebellar ataxia
De novo variant
Exome sequencing
Molecular mechanisms
Recessive ataxia
topic Cerebellar ataxia
De novo variant
Exome sequencing
Molecular mechanisms
Recessive ataxia
description © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
publishDate 2022
dc.date.none.fl_str_mv 2022-04-07T16:26:03Z
2022
2022-01-01T00:00:00Z
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/10451/52260
url http://hdl.handle.net/10451/52260
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Cells. 2022 Mar 12;11(6):981
10.3390/cells11060981
2073-4409
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 MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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