PARK7

protein-coding

Parkinsonism associated deglycase, the group of Glutamine amidotransferase class 1 domain containing

Gene summary

The product of this gene belongs to the peptidase C56 family of proteins. It acts as a positive regulator of androgen receptor-dependent transcription. It may also function as a redox-sensitive chaperone, as a sensor for oxidative stress, and it apparently protects neurons against oxidative stress and cell death. Defects in this gene are the cause of autosomal recessive early-onset Parkinson disease 7. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_007262.5

Inheritance

ClinVar variants

P:15U:55B:14

Top phenotype

Parkinson disease 7, autosomal recessive early-onset

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr1:7,954,291-7,985,505

External References & Databases

Ensembl (ENSG00000116288)

Transcript & Mutation Effects

hg38 • Region Span ~31.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive early-onset Parkinson disease 7MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011658

Submitter: Ambry Genetics

autosomal recessive early-onset Parkinson disease 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011658

Submitter: Labcorp Genetics (formerly Invitae)

Parkinson diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005180

Submitter: ClinGen

*PARK7* (also known as *DJ-1*) was first reported in relation to autosomal-recessive Parkinson´s disease in 2003 (Bonifati et al. 2003, PMID: 12446870). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine-producing neurons in the substantia nigra, and Lewy bodies in the substantia nigra and locus coeruleus are found in most cases. 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). Several pathogenic variants have been reported in >30 patients by different authors/groups from different ethnicities (Kasten et al. 2018, PMID: 29644727, www.mdsgene.org). The mutational spectrum is broad, including structural variants (exon deletions), nonsense, frameshift, splice site, and missense changes. Four of these publications are included in this curation covering multiplex families with mainly 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 seemingly full penetrance. This 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. It has further been shown that several of the missense variants are unstable (Görner et al. 2004, PMID: 14607841; Blackinton et al. 2005, PMID: 15790532; Malgieri and Eliezer, PMID: 18436956). *PARK7/DJ-1* encodes a declycase and has pleiotropic functions including roles as a chaperone with protease activity, a transcriptional regulator, and an antioxidant scavenger and redox sensor (Ottolini et al. 2013; PMID: 23418303). DJ-1 is also involved in tumorigenesis and in maintaining mitochondrial homeostasis. The encoded protein may interact with other autosomal-recessive Parkinson´s disease genes, including PRKN (Moore et al. 2005, PMID: 15525661) and PINK1 (Tang et al. 2006, PMID: 16632486). Dj1-null mice showed a significant decrease in locomotor activity upon oxidative stress as well as a significant loss of striatal dopaminergic neurons when compared to control mice. Restoration of Dj1 expression in Dj1-null mice resulted in a protective effect upon oxidative stress (Kim et al. 2005, PubMed: 15784737). In summary, biallelic, pathogenic variants in *PARK7/DJ-1* 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.

autosomal recessive early-onset Parkinson disease 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011658

Submitter: Genomics England PanelApp

young-onset Parkinson diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017279

Submitter: Orphanet

Clinical Genomic Database (CGD)

Parkinson disease 7, autosomal recessive early-onsetAR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Response to levodopa has been documented

Refs: 11462174; 11835383; 12953260; 12446870; 14638971; 16240358; 20837857; 21506293; 22956510

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PARK7 variants in ClinVar

13 Conditions Cataloged

Autosomal recessive early-onset Parkinson disease 7Total: 75

not providedTotal: 38

not specifiedTotal: 10

Inborn genetic diseasesTotal: 9

PARK7-related disorderTotal: 3

Juvenile-onset Parkinson diseaseTotal: 1

Young-onset Parkinson diseaseTotal: 1

PARK7-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007262.5. 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				11 clinvar		11
missense	5 clinvar	3 clinvar	49 clinvar	3 clinvar		60
nonsense	2 clinvar					2
start loss						0
frameshift	2 clinvar	2 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar	5 clinvar			6
Total	9	6	55	14	0	84

Highest pathogenic variant AF is 0.00012143095

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007262.5	RefSeq	NP_009193.2	6	MANE Select
ENST00000338639.10	Ensembl	ENSP00000340278.5	6	MANE Select
NM_001123377.2	RefSeq	NP_001116849.1	6	Standard
ENST00000377488.5	Ensembl	ENSP00000366708.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
park7	Danio rerio	Structure: post-vent region Quality: apoptotic abnormal

Gene / Model

Organism

Observed Phenotype

park7

Danio rerio

Structure: post-vent region

Quality: apoptotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Parkinson,s disease - Homo sapiens (human)
Androgen receptor signaling pathway
Synaptic Vesicle Pathway
Parkinsons Disease Pathway
AndrogenReceptor

Biological Process

negative regulation of protein phosphorylation
positive regulation of acute inflammatory response to antigenic stimulus
DNA repair
negative regulation of protein kinase activity
proteolysis

Molecular Function

core promoter binding
double-stranded DNA binding
single-stranded DNA binding
transcription coactivator activity
mRNA binding

Cellular Component

chromatin
nucleus
nucleoplasm
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000493678
Coding exons: 6
Length: 31215
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125748
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.165	104	109	0.956	0.00000613	1216
Missense (PolyPhen)		22	28.303	0.77729		333
Synonymous	0.342	37	39.7	0.931	0.00000234	389
Loss of Function	2.47	1	8.97	0.112	4.64e-7	108

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein and nucleotide deglycase that catalyzes the deglycation of the Maillard adducts formed between amino groups of proteins or nucleotides and reactive carbonyl groups of glyoxals (PubMed:25416785, PubMed:28596309). Thus, functions as a protein deglycase that repairs methylglyoxal- and glyoxal-glycated proteins, and releases repaired proteins and lactate or glycolate, respectively. Deglycates cysteine, arginine and lysine residues in proteins, and thus reactivates these proteins by reversing glycation by glyoxals. Acts on early glycation intermediates (hemithioacetals and aminocarbinols), preventing the formation of advanced glycation endproducts (AGE) that cause irreversible damage (PubMed:25416785, PubMed:28013050, PubMed:26995087). Also functions as a nucleotide deglycase able to repair glycated guanine in the free nucleotide pool (GTP, GDP, GMP, dGTP) and in DNA and RNA. Is thus involved in a major nucleotide repair system named guanine glycation repair (GG repair), dedicated to reversing methylglyoxal and glyoxal damage via nucleotide sanitization and direct nucleic acid repair (PubMed:28596309). Also displays an apparent glyoxalase activity that in fact reflects its deglycase activity (PubMed:22523093). Plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease; functions probably related to its primary function (PubMed:17015834, PubMed:20304780, PubMed:18711745, PubMed:12796482, PubMed:19229105, PubMed:25416785, PubMed:26995087). It is involved in neuroprotective mechanisms like the stabilization of NFE2L2 and PINK1 proteins, male fertility as a positive regulator of androgen signaling pathway as well as cell growth and transformation through, for instance, the modulation of NF-kappa-B signaling pathway (PubMed:12612053, PubMed:15502874, PubMed:14749723, PubMed:17015834, PubMed:21097510, PubMed:18711745). Eliminates hydrogen peroxide and protects cells against hydrogen peroxide-induced cell death (PubMed:16390825). Required for correct mitochondrial morphology and function as well as for autophagy of dysfunctional mitochondria (PubMed:19229105, PubMed:16632486). Plays a role in regulating expression or stability of the mitochondrial uncoupling proteins SLC25A14 and SLC25A27 in dopaminergic neurons of the substantia nigra pars compacta and attenuates the oxidative stress induced by calcium entry into the neurons via L-type channels during pacemaking (PubMed:18711745). Regulates astrocyte inflammatory responses, may modulate lipid rafts-dependent endocytosis in astrocytes and neuronal cells (PubMed:23847046). In pancreatic islets, involved in the maintenance of mitochondrial reactive oxygen species (ROS) levels and glucose homeostasis in an age- and diet dependent manner. Protects pancreatic beta cells from cell death induced by inflammatory and cytotoxic setting (By similarity). Binds to a number of mRNAs containing multiple copies of GG or CC motifs and partially inhibits their translation but dissociates following oxidative stress (PubMed:18626009). Metal- binding protein able to bind copper as well as toxic mercury ions, enhances the cell protection mechanism against induced metal toxicity (PubMed:23792957). In macrophages, interacts with the NADPH oxidase subunit NCF1 to direct NADPH oxidase-dependent ROS production, and protects against sepsis (By similarity). {ECO:0000250|UniProtKB:Q99LX0, ECO:0000269|PubMed:11477070, ECO:0000269|PubMed:12612053, ECO:0000269|PubMed:12855764, ECO:0000269|PubMed:12939276, ECO:0000269|PubMed:14749723, ECO:0000269|PubMed:15181200, ECO:0000269|PubMed:15502874, ECO:0000269|PubMed:15976810, ECO:0000269|PubMed:16390825, ECO:0000269|PubMed:17015834, ECO:0000269|PubMed:18626009, ECO:0000269|PubMed:18711745, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20186336, ECO:0000269|PubMed:20304780, ECO:0000269|PubMed:21097510, ECO:0000269|PubMed:22523093, ECO:0000269|PubMed:23792957, ECO:0000269|PubMed:23847046, ECO:0000269|PubMed:25416785, ECO:0000269|PubMed:26995087, ECO:0000269|PubMed:28013050, ECO:0000269|PubMed:28596309, ECO:0000269|PubMed:9070310}.;
Disease: DISEASE: Parkinson disease 7 (PARK7) [MIM:606324]: A neurodegenerative disorder characterized by resting tremor, postural tremor, bradykinesia, muscular rigidity, anxiety and psychotic episodes. PARK7 has onset before 40 years, slow progression and initial good response to levodopa. Some patients may show traits reminiscent of amyotrophic lateral sclerosis- parkinsonism/dementia complex (Guam disease). {ECO:0000269|PubMed:12446870, ECO:0000269|PubMed:12851414, ECO:0000269|PubMed:12953260, ECO:0000269|PubMed:14607841, ECO:0000269|PubMed:14713311, ECO:0000269|PubMed:15254937, ECO:0000269|PubMed:15365989, ECO:0000269|PubMed:17846173, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:22523093, ECO:0000269|PubMed:23792957, ECO:0000269|PubMed:23847046}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.541

Intolerance Scores

LoFtool: 0.129
RVIS EVS: 0.08
RVIS percentile EVS: 60.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.979

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium