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



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.



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.



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.
aNational Health Institute Doutor Ricardo Jorge bBiosystems and Integrative Sciences Institute (BioISI), Lisboa cInstituto Gulbenkian de Ciência, Oeiras dUnidade de Neurodesenvolvimento e Autismo, Centro de Desenvolvimento da Criança e Centro Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e University of Coimbra, Coimbra eInstitute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Inês C
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Maria M
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Bárbara
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Oliveira
Cátia
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Café
Joana
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Susana
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Mouga
Frederico
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Duque
Guiomar
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Oliveira
Astrid M
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Vicente
D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011174:Portugal; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein