PRKN

protein-coding

parkin RBR E3 ubiquitin protein ligase, the group of RBR E3 ubiquitin ligases

Gene summary

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. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

Previous symbols:

PARK2

MANE transcript

NM_004562.3

Inheritance

ClinVar variants

P:56U:174B:93

Top phenotype

Parkinson disease 2, autosomal recessive juvenile

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr6:161,347,417-162,727,775

External References & Databases

Ensembl (ENSG00000185345)

Transcript & Mutation Effects

hg38 • Region Span ~1,380.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive juvenile Parkinson disease 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010820

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Parkinson diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005180

Submitter: ClinGen

PRKN (also known as Parkin or PARK2) was first reported in relation to autosomal-recessive Parkinson´s disease in 1998 (Kitada et al. 1998, PMID: 9560156). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine-producing neurons in the substantia nigra. Signs and symptoms include tremor, which is most pronounced during rest, muscle rigidity, slowing of voluntary movements (bradykinesia), and a tendency to fall back (postural instability). Many PRKN pathogenic variants in the biallelic state have been reported in >1000 patients by different authors/groups from different ethnicities (Kasten et al. 2018, PMID: 29644727, www.mdsgene.org). The mutational spectrum is broad, often including structural variants (e.g. exon deletions), nonsense, frameshift, splice site, and missense changes. Four multiplex families from three publications are included in this curation, covering patients with biallelic truncating variants. The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence (12 pts.) has been reached. The disease follows a recessive mode of inheritance with almost full, but age-dependent penetrance (Deng et al. 2006, PMID: 16476817; Qin et al. 2014, PMID: 25404955; www.medgene.org). Notably, there is an ongoing debate on the potential role of heterozygous variants as genetic risk factors for Parkinson´s disease (Klein et al. 2007, PMID: 17582365; Zhu et al. 2022, PMID: 35640906). The gene-disease association is also supported by recurrent experimental evidence, including animal models and in-vitro functional assays. The mechanism of pathogenicity appears to be a loss-of-function (LOF) indicated by the many truncating variants and further supported by knock-out fly models (Greene et al., PMID: 12642658). There is a well-defined functional interaction with another autosomal-recessive Parkinson´s disease-linked gene, i.e. PINK1. While PINK1 functions as a sensor for disrupted mitochondria, the PRKN-encoded Parkin protein as an E3-ubiquitin ligase is involved in labeling such mitochondria for degradation (Narendra et al. 2010, PMID: 20126261; Rakovic et al. 2010, PMID: 20508036). It has further repeatedly been shown that several of the PRKN missense variants have impaired ubiquitination properties and impair proper mitophagy (e.g. Sriram et al. 2005, PMID: 16049031; Hampe et al. 2006, PMID: 16714300; Lee et al. 2010; PMID: 20457763; Chaugule et al. 2011, PMID: 21694720; Yi et al. 2019, PMID: 30994895). PRKN overexpression was shown to rescue the phenotype in PINK1 mutant flies (Park et al. 2006, PMID: 16672980). In summary, biallelic, pathogenic variants in PRKN are definitively causing autosomal-recessive Parkinson´s disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

young-onset Parkinson diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017279

Submitter: Orphanet

autosomal recessive juvenile Parkinson disease 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010820

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Parkinson disease 2, autosomal recessive juvenileAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Individuals have been reported as responding to therapies such as levodopa

Refs: 9560156; 10894217; 11487568; 11552035; 12056932; 12629236; 12891670; 12730996; 15266615; 15642918; 16130111; 16328510; 17187375; 20182943; 20837857; 20876472; 20558392

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKN variants in ClinVar

22 Conditions Cataloged

not providedTotal: 319

Autosomal recessive juvenile Parkinson disease 2Total: 96

Inborn genetic diseasesTotal: 70

Lung cancerTotal: 30

not specifiedTotal: 23

Ovarian cancerTotal: 17

Ovarian neoplasmTotal: 15

PRKN-related disorderTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004562.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	69 clinvar	1 clinvar	78
missense	7 clinvar	12 clinvar	165 clinvar	19 clinvar	4 clinvar	207
nonsense	7 clinvar	4 clinvar				11
start loss		2 clinvar				2
frameshift	8 clinvar	9 clinvar				17
splice donor/acceptor (+/-2bp)	4 clinvar	3 clinvar	1 clinvar			8
Total	26	30	174	88	5	323

Highest pathogenic variant AF is 0.003009264

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004562.3	RefSeq	NP_004553.2	12	MANE Select
ENST00000366898.6	Ensembl	ENSP00000355865.1	12	MANE Select
NM_013987.3	RefSeq	NP_054642.2	11	Standard
NM_013988.3	RefSeq	NP_054643.2	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
prkn	Danio rerio	Structure: fast muscle cell Quality: unlumenized abnormal

Gene / Model

Organism

Observed Phenotype

prkn

Danio rerio

Structure: fast muscle cell

Quality: unlumenized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Protein processing in endoplasmic reticulum - Homo sapiens (human)
Mitophagy - animal - Homo sapiens (human)
Parkinson,s disease - Homo sapiens (human)
Parkin-Ubiquitin Proteasomal System pathway

Biological Process

negative regulation of transcription by RNA polymerase II
protein polyubiquitination
mitochondrial fission
autophagy of mitochondrion
mitophagy

Molecular Function

transcription regulatory region sequence-specific DNA binding
DNA-binding transcription repressor activity, RNA polymerase II-specific
G protein-coupled receptor binding
actin binding
ubiquitin-protein transferase activity

Cellular Component

ubiquitin ligase complex
nucleus
cytoplasm
mitochondrion
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366898
Coding exons: 12
Length: 1380352
Individuals with no LoFs: 125552
Homozygous LoFs: 0
Heterozygous LoFs: 196
Defined: 125748
p: 0.000780

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.863	310	270	1.15	0.0000165	3049
Missense (PolyPhen)		131	120.84	1.0841		1359
Synonymous	-1.23	124	108	1.15	0.00000745	866
Loss of Function	2.10	14	25.4	0.551	0.00000119	303

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.0014	0.0014	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.0010	0.0010	notable
South Asian	0.00020	0.00020	rare
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2 (PubMed:10973942, PubMed:10888878, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:16135753, PubMed:21376232, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'- linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'- linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11590439, PubMed:11431533, PubMed:19229105, PubMed:11590439, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (PubMed:25621951). Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in the regulation of neuron death (PubMed:21376232). Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene. {ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10973942, ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:12628165, ECO:0000269|PubMed:12719539, ECO:0000269|PubMed:15105460, ECO:0000269|PubMed:15728840, ECO:0000269|PubMed:16135753, ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:18541373, ECO:0000269|PubMed:19029340, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:21532592, ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:25527291, ECO:0000269|PubMed:25621951}.;
Disease: DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:19966284}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996 and PubMed:12629236).; DISEASE: Parkinson disease 2 (PARK2) [MIM:600116]: A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA- induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent. {ECO:0000269|PubMed:10072423, ECO:0000269|PubMed:10824074, ECO:0000269|PubMed:10888878, ECO:0000269|PubMed:10939576, ECO:0000269|PubMed:11163284, ECO:0000269|PubMed:11179010, ECO:0000269|PubMed:11431533, ECO:0000269|PubMed:11487568, ECO:0000269|PubMed:11590439, ECO:0000269|PubMed:11971093, ECO:0000269|PubMed:12056932, ECO:0000269|PubMed:12112109, ECO:0000269|PubMed:12114481, ECO:0000269|PubMed:12116199, ECO:0000269|PubMed:12362318, ECO:0000269|PubMed:12397156, ECO:0000269|PubMed:12629236, ECO:0000269|PubMed:12730996, ECO:0000269|PubMed:12925569, ECO:0000269|PubMed:15584030, ECO:0000269|PubMed:17360614, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20889486, ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:21376232, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:9560156, ECO:0000269|PubMed:9731209}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in PRKN may be involved in the development and/or progression of ovarian cancer.;

Recessive Scores

pRec: 0.478

Intolerance Scores

RVIS EVS: 1.31
RVIS percentile EVS: 94.04

Essentials

Essential (gene trap): N