Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure
Autor(a) principal: | |
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Data de Publicação: | 2016 |
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/10400.18/4157 |
Resumo: | Objective: The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson’s disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. Materials and methods: To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. Results: Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. Conclusion: Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains. |
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Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structureAutism Spectrum DisorderCopy Number VariantsPARK2 geneParkinVariant PathogenicityPerturbações do Desenvolvimento Infantil e Saúde MentalObjective: The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson’s disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. Materials and methods: To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. Results: Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. Conclusion: Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains.Inês C. Conceição was supported by grant SFRH/BPD/74739/2010 from Fundação para a Ciência e Tecnologia (Portugal).Wolters Kluwer Health, IncRepositório Científico do Instituto Nacional de SaúdeConceição, I.C.Rama, M.M.Oliveira, B.Café, C.Almeida, J.Mouga, S.Duque, F.Oliveira, G.Vicente, A.M.2017-11-08T01:30:14Z2016-11-072016-11-07T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/4157engPsychiatr Genet. 2017 Apr;27(2):54-61. doi: 10.1097/YPG.0000000000000159. [Epub 2016 Nov 7]0955-882910.1097/YPG.0000000000000159info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:40:19ZPortal AgregadorONG |
dc.title.none.fl_str_mv |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
title |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
spellingShingle |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure Conceição, I.C. Autism Spectrum Disorder Copy Number Variants PARK2 gene Parkin Variant Pathogenicity Perturbações do Desenvolvimento Infantil e Saúde Mental |
title_short |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
title_full |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
title_fullStr |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
title_full_unstemmed |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
title_sort |
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure |
author |
Conceição, I.C. |
author_facet |
Conceição, I.C. Rama, M.M. Oliveira, B. Café, C. Almeida, J. Mouga, S. Duque, F. Oliveira, G. Vicente, A.M. |
author_role |
author |
author2 |
Rama, M.M. Oliveira, B. Café, C. Almeida, J. Mouga, S. Duque, F. Oliveira, G. Vicente, A.M. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Conceição, I.C. Rama, M.M. Oliveira, B. Café, C. Almeida, J. Mouga, S. Duque, F. Oliveira, G. Vicente, A.M. |
dc.subject.por.fl_str_mv |
Autism Spectrum Disorder Copy Number Variants PARK2 gene Parkin Variant Pathogenicity Perturbações do Desenvolvimento Infantil e Saúde Mental |
topic |
Autism Spectrum Disorder Copy Number Variants PARK2 gene Parkin Variant Pathogenicity Perturbações do Desenvolvimento Infantil e Saúde Mental |
description |
Objective: The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson’s disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. Materials and methods: To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. Results: Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. Conclusion: Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-11-07 2016-11-07T00:00:00Z 2017-11-08T01:30:14Z |
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/10400.18/4157 |
url |
http://hdl.handle.net/10400.18/4157 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Psychiatr Genet. 2017 Apr;27(2):54-61. doi: 10.1097/YPG.0000000000000159. [Epub 2016 Nov 7] 0955-8829 10.1097/YPG.0000000000000159 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Wolters Kluwer Health, Inc |
publisher.none.fl_str_mv |
Wolters Kluwer Health, Inc |
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 |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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