Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure

OBJECTIVEThe 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 neur...

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Published in:	Psychiatric genetics Vol. 27; no. 2; pp. 54 - 61
Main Authors:	Conceição, Inês C, Rama, Maria M, Oliveira, Bárbara, Café, Cátia, Almeida, Joana, Mouga, Susana, Duque, Frederico, Oliveira, Guiomar, Vicente, Astrid M
Format:	Journal Article
Language:	English
Published:	England Copyright Wolters Kluwer Health, Inc. All rights reserved 01-04-2017
Subjects:	Autism Spectrum Disorder - genetics Autism Spectrum Disorder - metabolism Computer Simulation DNA Copy Number Variations Female Humans Male Mutation Neurodevelopmental Disorders - genetics Neurodevelopmental Disorders - metabolism Parkinson Disease - genetics Parkinson Disease - metabolism Portugal Structure-Activity Relationship Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism
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Summary:	OBJECTIVEThe 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 METHODSTo 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. RESULTSOverall, 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. CONCLUSIONAlthough 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0955-8829 1473-5873
DOI:	10.1097/YPG.0000000000000159