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UniProtKB/Swiss-Prot O60260: Variant p.Arg275Trp

E3 ubiquitin-protein ligase parkin
Gene: PRKN
Variant information

Variant position:  275
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Tryptophan (W) at position 275 (R275W, p.Arg275Trp).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and basic (R) to large size and aromatic (W)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in 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, ECO:0000269|PubMed:29311685}. 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).
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In PARK2 and PARK; at heterozygosity it is associated with late onset Parkinson disease; impairs the ability to ubiquitinate SNCAIP; abolishes p53/TP53 transcriptional repression; impairs the ability to ubiquitinate and degrade SYT11.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.

Sequence information

Variant position:  275
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  465
The length of the canonical sequence.

The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.




Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

Chain 1 – 465 E3 ubiquitin-protein ligase parkin
Zinc finger 238 – 293 RING-type 1
Region 234 – 465 TRIAD supradomain
Region 257 – 293 SYT11 binding 2
Metal binding 257 – 257 Zinc 2; via pros nitrogen
Metal binding 260 – 260 Zinc 1
Metal binding 263 – 263 Zinc 1
Metal binding 289 – 289 Zinc 2
Metal binding 293 – 293 Zinc 2
Alternative sequence 290 – 290 V -> VGTGDTVVLRGALGGFRRGV. In isoform 5.

Literature citations

Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease.
Chung K.K.K.; Zhang Y.; Lim K.L.; Tanaka Y.; Huang H.; Gao J.; Ross C.A.; Dawson V.L.; Dawson T.M.;
Nat. Med. 7:1144-1150(2001)

Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease.
da Costa C.A.; Sunyach C.; Giaime E.; West A.; Corti O.; Brice A.; Safe S.; Abou-Sleiman P.M.; Wood N.W.; Takahashi H.; Goldberg M.S.; Shen J.; Checler F.;
Nat. Cell Biol. 11:1370-1375(2009)

PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease.
Shin J.H.; Ko H.S.; Kang H.; Lee Y.; Lee Y.I.; Pletinkova O.; Troconso J.C.; Dawson V.L.; Dawson T.M.;
Cell 144:689-702(2011)

A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe.
Abbas N.; Luecking C.B.; Ricard S.; Duerr A.; Bonifati V.; De Michele G.; Bouley S.; Vaughan J.R.; Gasser T.; Marconi R.; Broussolle E.; Brefel-Courbon C.; Harhangi B.S.; Oostra B.A.; Fabrizio E.; Bohme G.A.; Pradier L.; Wood N.W.; Filla A.; Meco G.; Denefle P.; Agid Y.; Brice A.;
Hum. Mol. Genet. 8:567-574(1999)
Cited for: VARIANTS PARK2 ASN-161; CYS-256; TRP-275 AND ASN-415; VARIANTS ASN-167; LEU-380 AND ASN-394;

Association between early-onset Parkinson's disease and mutations in the parkin gene.
Luecking C.B.; Duerr A.; Bonifati V.; Vaughan J.R.; De Michele G.; Gasser T.; Harhangi B.S.; Meco G.; Denefle P.; Wood N.W.; Agid Y.; Brice A.;
N. Engl. J. Med. 342:1560-1567(2000)
Cited for: VARIANTS PARK2 ASN-161; ASN-211; CYS-256; TRP-275; ASN-280; GLY-289; GLU-328; ASN-415 AND ASP-430; VARIANT CYS-334;

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from founder effects.
Periquet M.; Luecking C.B.; Vaughan J.R.; Bonifati V.; Duerr A.; De Michele G.; Horstink M.; Farrer M.; Illarioshkin S.N.; Pollak P.; Borg M.; Brefel-Courbon C.; Denefle P.; Meco G.; Gasser T.; Breteler M.M.; Wood N.W.; Agid Y.; Brice A.;
Am. J. Hum. Genet. 68:617-626(2001)
Cited for: VARIANTS PARK2 ASN-211; TRP-275 AND ASP-430;

Complex relationship between parkin mutations and Parkinson disease.
West A.; Periquet M.; Lincoln S.; Luecking C.B.; Nicholl D.; Bonifati V.; Rawal N.; Gasser T.; Lohmann E.; Deleuze J.-F.; Maraganore D.; Levey A.; Wood N.W.; Duerr A.; Hardy J.; Brice A.; Farrer M.;
Am. J. Med. Genet. 114:584-591(2002)
Cited for: VARIANTS PARK2 GLU-82; CYS-256; TRP-275; GLU-328 AND ARG-441;

Linkage stratification and mutation analysis at the parkin locus identifies mutation positive Parkinson's disease families.
Nichols W.C.; Pankratz N.; Uniacke S.K.; Pauciulo M.W.; Halter C.; Rudolph A.; Conneally P.M.; Foroud T.;
J. Med. Genet. 39:489-492(2002)
Cited for: VARIANTS PARK2 ASN-211; TRP-275; ASP-430 AND LEU-437;

Evaluation of 50 probands with early-onset Parkinson's disease for parkin mutations.
Hedrich K.; Marder K.; Harris J.; Kann M.; Lynch T.; Meija-Santana H.; Pramstaller P.P.; Schwinger E.; Bressman S.B.; Fahn S.; Klein C.;
Neurology 58:1239-1246(2002)
Cited for: VARIANTS PARK2 PRO-42; LEU-192; CYS-256; TRP-275; ASP-430 AND LEU-437;

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.
Oliveira S.A.; Scott W.K.; Martin E.R.; Nance M.A.; Watts R.L.; Hubble J.P.; Koller W.C.; Pahwa R.; Stern M.B.; Hiner B.C.; Ondo W.G.; Allen F.H. Jr.; Scott B.L.; Goetz C.G.; Small G.W.; Mastaglia F.; Stajich J.M.; Zhang F.; Booze M.W.; Winn M.P.; Middleton L.T.; Haines J.L.; Pericak-Vance M.A.; Vance J.M.;
Ann. Neurol. 53:624-629(2003)
Cited for: VARIANTS PARK2 GLN-33; GLU-82; ASP-430 AND LEU-437; VARIANTS PARK TYR-253; CYS-256; TRP-275 AND ASN-280; VARIANTS LEU-380 AND ASN-394;

Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease.
Kilarski L.L.; Pearson J.P.; Newsway V.; Majounie E.; Knipe M.D.; Misbahuddin A.; Chinnery P.F.; Burn D.J.; Clarke C.E.; Marion M.H.; Lewthwaite A.J.; Nicholl D.J.; Wood N.W.; Morrison K.E.; Williams-Gray C.H.; Evans J.R.; Sawcer S.J.; Barker R.A.; Wickremaratchi M.M.; Ben-Shlomo Y.; Williams N.M.; Morris H.R.;
Mov. Disord. 27:1522-1529(2012)
Cited for: VARIANT PARK2 TRP-275;

Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson's disease-like pathology.
Wang C.; Kang X.; Zhou L.; Chai Z.; Wu Q.; Huang R.; Xu H.; Hu M.; Sun X.; Sun S.; Li J.; Jiao R.; Zuo P.; Zheng L.; Yue Z.; Zhou Z.;
Nat. Commun. 9:81-81(2018)

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.