Human Gene Module / Chromosome 6 / PRKN

PRKNparkin RBR E3 ubiquitin protein ligase

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 15
Rare Variants / Common Variants
22 / 3
Aliases
PRKN, AR-JP,  LPRS2,  PARK2,  PDJ
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
6q26
Associated Disorders
ID
Relevance to Autism

In a genome-wide study, association was found between CNVs in the PRKN gene and autism in AGRE and ACC cohorts (European ancestry) (Glessner et al., 2009). In addition, a rare duplication in the PRKN gene has been identified in an individual with ASD (ORoak et al., 2012). As well, rare variants in the PRKN gene have been identified in individuals with autosomal recessive juvenile parkinsonism (Kitada et al., 1998).

Molecular Function

The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease.

Reports related to PRKN (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Shimura H , et al. (2000) No -
2 Highly Cited Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Shimura H , et al. (2001) No -
3 Highly Cited An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Imai Y , et al. (2001) No -
4 Recent Recommendation Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic... Lu XH , et al. (2009) No -
5 Recent Recommendation Identification of a novel Zn2+binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. Hristova VA , et al. (2009) No -
6 Primary Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Glessner JT , et al. (2009) Yes -
7 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
8 Support Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Jarick I , et al. (2012) No -
9 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
10 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
11 Support Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders. Nava C , et al. (2013) Yes ID
12 Support Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder. Yin CL , et al. (2016) Yes -
13 Support Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through insilico analysis of its functional structure. Conceio IC , et al. (2016) Yes -
14 Positive Association Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts. Zhang X , et al. (2019) No -
15 Highly Cited Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Kitada T , et al. (1998) No -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Simplex 23632794 Nava C , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain De novo - Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 27042285 Yin CL , et al. (2016)
- - copy_number_loss Familial Paternal Multiplex 9560156 Kitada T , et al. (1998)
- - copy_number_gain Familial Maternal Multiplex 23632794 Nava C , et al. (2013)
- - copy_number_loss Familial Paternal Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Unknown Not maternal Simplex 27042285 Yin CL , et al. (2016)
- - copy_number_gain Familial Paternal Simplex 22495309 O'Roak BJ , et al. (2012)
- - copy_number_loss Familial Both parents Simplex 9560156 Kitada T , et al. (1998)
- - copy_number_loss Familial Maternal Simplex 27824727 Conceio IC , et al. (2016)
- - copy_number_loss Familial Paternal Simplex 27824727 Conceio IC , et al. (2016)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 27824727 Conceio IC , et al. (2016)
- - copy_number_gain Familial Paternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Multi-generational 27042285 Yin CL , et al. (2016)
- - copy_number_loss Familial Maternal Multi-generational 27824727 Conceio IC , et al. (2016)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 31003785 Zhang X , et al. (2019)
- - copy_number_loss - - - 19404257 Glessner JT , et al. (2009)
- - copy_number_variation - - - 23164820 Jarick I , et al. (2012)
SFARI Gene score
2

Strong Candidate

Deletions affecting PRKN (formerly known as PARK2) were observed in 7 cases (discovery and replication datasets) but not in controls (P=0.0047) in Glessner et al., 2009; 1/7 variants were confirmed by qPCR, but the status of the remainder is unknown (P value of 3.3 x 10-3 is for genes within GO term "ubiquitin conjugation", not PRKN alone), and gene-level statistical support was only nominal in this report. A total of 24 PRKN exon-disrupting CNVs (12 deletions, 12 duplications) were detected in a cohort of 2,588 ASD cases compared to a total of 10 exon-disrupting CNVs (5 deletions, 5 duplications) in 2670 controls (p=0.009) in Girirajan et al. 2013. A genome-wide analysis of CNVs in a Han Chinese ASD cohort in Yin et al., 2016 determined that the frequency of exonic CNVs at the PRKN locus was significantly greater in ASD cases (6/636) than in ethnically-matched controls (2/1394; P=0.014). Comparison of the frequencies of PRKN CNVs in NDD cases and controls in Conceicao et al., 2016 demonstrated that NDD patients had a higher frequency of CNVs containing exons 5-12 of the PRKN gene (26.8%) than did controls (2.4%; P=0.0003). However, in many cases PRKN CNVs from these studies were predominantly inherited and displayed incomplete penetrance with ASD. CNVs within the PRKN locus were also found to be significantly more prevalent in German ADHD patients in both discovery (P=2.8E-04) and replication (P=4.3E-2) samples than in controls (Jarick et al., 2014). OMIM indicates that autosomal recessive mutations in this gene result in juvenile onset Parkinsons disease. A meta-analysis of 5,780 cases with major depressive disorder (MDD) and 6,626 controls from four cohorts in Zhang et al., 2019 identified a CNV region containing exonic and intronic deletions in the PRKN gene that was statistically enriched in MDD cases compared with controls (65 in cases vs. 40 in controls; odds ratio 1.92, P-value 9.7E-04).

Score Delta: Score remained at 3

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2019
3
icon
3

Score remained at 3

Description

2019 Q3 Rescoring regime

7/1/2018
icon
3

Increased from to 3

Description

Deletions affecting PRKN (formerly known as PARK2) were observed in 7 cases (discovery and replication datasets) but not in controls (P=0.0047) in Glessner et al., 2009; 1/7 variants were confirmed by qPCR, but the status of the remainder is unknown (P value of 3.3 x 10-3 is for genes within GO term "ubiquitin conjugation", not PRKN alone), and gene-level statistical support was only nominal in this report. A total of 24 PRKN exon-disrupting CNVs (12 deletions, 12 duplications) were detected in a cohort of 2,588 ASD cases compared to a total of 10 exon-disrupting CNVs (5 deletions, 5 duplications) in 2670 controls (p=0.009) in Girirajan et al. 2013. A genome-wide analysis of CNVs in a Han Chinese ASD cohort in Yin et al., 2016 determined that the frequency of exonic CNVs at the PRKN locus was significantly greater in ASD cases (6/636) than in ethnically-matched controls (2/1394; P=0.014). Comparison of the frequencies of PRKN CNVs in NDD cases and controls in Conceicao et al., 2016 demonstrated that NDD patients had a higher frequency of CNVs containing exons 5-12 of the PRKN gene (26.8%) than did controls (2.4%; P=0.0003). However, in many cases PRKN CNVs from these studies were predominantly inherited and displayed incomplete penetrance with ASD. CNVs within the PRKN locus were also found to be significantly more prevalent in German ADHD patients in both discovery (P=2.8E-04) and replication (P=4.3E-2) samples than in controls (Jarick et al., 2014). OMIM indicates that autosomal recessive mutations in this gene result in juvenile onset Parkinsons disease.

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