Home  |  Contact

UniProtKB/Swiss-Prot Q5S007: Variant p.Gly2019Ser

Leucine-rich repeat serine/threonine-protein kinase 2
Gene: LRRK2
Chromosomal location: 12q12
Variant information

Variant position:  2019
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 Glycine (G) to Serine (S) at position 2019 (G2019S, p.Gly2019Ser).
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 glycine (G) to small size and polar (S)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
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 8 (PARK8) [MIM:607060]: A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. {ECO:0000269|PubMed:15541308, ECO:0000269|PubMed:15541309, ECO:0000269|PubMed:15680455, ECO:0000269|PubMed:15680456, ECO:0000269|PubMed:15680457, ECO:0000269|PubMed:15726496, ECO:0000269|PubMed:15732108, ECO:0000269|PubMed:15811454, ECO:0000269|PubMed:15852371, ECO:0000269|PubMed:15880653, ECO:0000269|PubMed:15925109, ECO:0000269|PubMed:15929036, ECO:0000269|PubMed:16102999, ECO:0000269|PubMed:16157901, ECO:0000269|PubMed:16157908, ECO:0000269|PubMed:16157909, ECO:0000269|PubMed:16172858, ECO:0000269|PubMed:16240353, ECO:0000269|PubMed:16247070, ECO:0000269|PubMed:16250030, ECO:0000269|PubMed:16251215, ECO:0000269|PubMed:16269541, ECO:0000269|PubMed:16272164, ECO:0000269|PubMed:16272257, ECO:0000269|PubMed:16298482, ECO:0000269|PubMed:16321986, ECO:0000269|PubMed:16333314, ECO:0000269|PubMed:16533964, ECO:0000269|PubMed:17114044, ECO:0000269|PubMed:18213618, ECO:0000269|PubMed:21850687, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:23395371, ECO:0000269|PubMed:25201882}. 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.

Variant description:  In PARK8; shows an increase in activity in both autophosphorylation and phosphorylation of a generic substrate; results in increased PRDX3 phosphorylation promoting dysregulation of mitochondrial function and oxidative damage; does not inhibit interaction with RAB29; shows a progressive reduction in neurite length and branching; shows distinctive spheroid-like inclusions within both neuronal processes and at intracellular membranous structures; shows lysosomal swelling and reduced retrograde transport of selective cargo between lysosomes and the Golgi apparatus; shows apoptotic mechanism of cell death; no loss of interaction with SEC16A.
Any additional useful information about the variant.

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

Sequence information

Variant position:  2019
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  2527
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 – 2527 Leucine-rich repeat serine/threonine-protein kinase 2
Domain 1879 – 2138 Protein kinase

Literature citations

Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
West A.B.; Moore D.J.; Biskup S.; Bugayenko A.; Smith W.W.; Ross C.A.; Dawson V.L.; Dawson T.M.;
Proc. Natl. Acad. Sci. U.S.A. 102:16842-16847(2005)

The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
MacLeod D.; Dowman J.; Hammond R.; Leete T.; Inoue K.; Abeliovich A.;
Neuron 52:587-593(2006)

Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
Angeles D.C.; Gan B.H.; Onstead L.; Zhao Y.; Lim K.L.; Dachsel J.; Melrose H.; Farrer M.; Wszolek Z.K.; Dickson D.W.; Tan E.K.;
Hum. Mutat. 32:1390-1397(2011)

RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
MacLeod D.A.; Rhinn H.; Kuwahara T.; Zolin A.; Di Paolo G.; McCabe B.D.; MacCabe B.D.; Marder K.S.; Honig L.S.; Clark L.N.; Small S.A.; Abeliovich A.;
Neuron 77:425-439(2013)

Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.
Kachergus J.M.; Mata I.F.; Hulihan M.; Taylor J.P.; Lincoln S.; Aasly J.O.; Gibson J.M.; Ross O.A.; Lynch T.; Wiley J.; Payami H.; Nutt J.; Maraganore D.M.; Czyzewski K.; Styczynska M.; Wszolek Z.K.; Farrer M.J.; Toft M.;
Am. J. Hum. Genet. 76:672-680(2005)
Cited for: VARIANT PARK8 SER-2019;

Clinical and positron emission tomography of Parkinson's disease caused by LRRK2.
Hernandez D.G.; Paisan-Ruiz C.; McInerney-Leo A.; Jain S.; Meyer-Lindenberg A.; Evans E.W.; Berman K.F.; Johnson J.; Auburger G.; Schaeffer A.A.; Lopez G.J.; Nussbaum R.L.; Singleton A.B.;
Ann. Neurol. 57:453-456(2005)
Cited for: VARIANT PARK8 SER-2019;

Clinical features of LRRK2-associated Parkinson's disease in central Norway.
Aasly J.O.; Toft M.; Fernandez-Mata I.; Kachergus J.M.; Hulihan M.; White L.R.; Farrer M.J.;
Ann. Neurol. 57:762-765(2005)
Cited for: VARIANT PARK8/PD SER-2019;

G2019S LRRK2 mutation in French and North African families with Parkinson's disease.
Lesage S.; Ibanez P.; Lohmann E.; Pollak P.; Tison F.; Tazir M.; Leutenegger A.-L.; Guimaraes J.; Bonnet A.-M.; Agid Y.; Duerr A.; Brice A.;
Ann. Neurol. 58:784-787(2005)
Cited for: VARIANT PARK8 SER-2019;

Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation.
Deng H.; Le W.; Guo Y.; Hunter C.B.; Xie W.; Jankovic J.;
Ann. Neurol. 57:933-934(2005)
Cited for: VARIANT PARK8 SER-2019;

Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease.
Berg D.; Schweitzer K.; Leitner P.; Zimprich A.; Lichtner P.; Belcredi P.; Bruessel T.; Schulte C.; Maass S.; Naegele T.;
Brain 128:3000-3011(2005)
Cited for: VARIANTS PARK8 MET-793; ARG-930; CYS-1096 THR-1228; SER-2019 AND THR-2020; VARIANT LYS-551;

Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.
Khan N.L.; Jain S.; Lynch J.M.; Pavese N.; Abou-Sleiman P.M.; Holton J.L.; Healy D.G.; Gilks W.P.; Sweeney M.G.; Ganguly M.; Gibbons V.; Gandhi S.; Vaughan J.; Eunson L.H.; Katzenschlager R.; Gayton J.; Lennox G.; Revesz T.; Nicholl D.; Bhatia K.P.; Quinn N.; Brooks D.; Lees A.J.; Davis M.B.; Piccini P.; Singleton A.B.; Wood N.W.;
Brain 128:2786-2796(2005)
Cited for: VARIANTS PARK8 CYS-1699; HIS-1941; SER-2019 AND ILE-2356;

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.
Di Fonzo A.; Tassorelli C.; De Mari M.; Chien H.F.; Ferreira J.; Rohe C.F.; Riboldazzi G.; Antonini A.; Albani G.; Mauro A.; Marconi R.; Abbruzzese G.; Lopiano L.; Fincati E.; Guidi M.; Marini P.; Stocchi F.; Onofrj M.; Toni V.; Tinazzi M.; Fabbrini G.; Lamberti P.; Vanacore N.; Meco G.; Leitner P.; Uitti R.J.; Wszolek Z.K.; Gasser T.; Simons E.J.; Breedveld G.J.; Goldwurm S.; Pezzoli G.; Sampaio C.; Barbosa E.; Martignoni E.; Oostra B.A.; Bonifati V.;
Eur. J. Hum. Genet. 14:322-331(2006)
Cited for: VARIANTS PARK8 VAL-1371; CYS-1441 AND SER-2019;

The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor.
Goldwurm S.; Di Fonzo A.; Simons E.J.; Rohe C.F.; Zini M.; Canesi M.; Tesei S.; Zecchinelli A.; Antonini A.; Mariani C.; Meucci N.; Sacilotto G.; Sironi F.; Salani G.; Ferreira J.; Chien H.F.; Fabrizio E.; Vanacore N.; Dalla Libera A.; Stocchi F.; Diroma C.; Lamberti P.; Sampaio C.; Meco G.; Barbosa E.; Bertoli-Avella A.M.; Breedveld G.J.; Oostra B.A.; Pezzoli G.; Bonifati V.;
J. Med. Genet. 42:E65-E65(2005)
Cited for: VARIANT PARK8 SER-2019;

Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.
Nichols W.C.; Pankratz N.; Hernandez D.; Paisan-Ruiz C.; Jain S.; Halter C.A.; Michaels V.E.; Reed T.; Rudolph A.; Shults C.W.; Singleton A.; Foroud T.;
Lancet 365:410-412(2005)
Cited for: VARIANT PARK8 SER-2019;

A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.
Di Fonzo A.; Rohe C.F.; Ferreira J.; Chien H.F.; Vacca L.; Stocchi F.; Guedes L.; Fabrizio E.; Manfredi M.; Vanacore N.; Goldwurm S.; Breedveld G.J.; Sampaio C.; Meco G.; Barbosa E.; Oostra B.A.; Bonifati V.;
Lancet 365:412-415(2005)
Cited for: VARIANT PARK8 SER-2019;

A common LRRK2 mutation in idiopathic Parkinson's disease.
Gilks W.P.; Abou-Sleiman P.M.; Gandhi S.; Jain S.; Singleton A.; Lees A.J.; Shaw K.; Bhatia K.P.; Bonifati V.; Quinn N.P.; Lynch J.M.; Healy D.G.; Holton J.L.; Revesz T.; Wood N.W.;
Lancet 365:415-416(2005)
Cited for: VARIANT PARK8 SER-2019;

LRRK2 mutations and Parkinsonism.
Toft M.; Mata I.F.; Kachergus J.M.; Ross O.A.; Farrer M.J.;
Lancet 365:1229-1230(2005)
Cited for: VARIANT PARK8 SER-2019;

Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation.
Kay D.M.; Kramer P.; Higgins D.S.; Zabetian C.P.; Payami H.;
Mov. Disord. 20:1077-1078(2005)
Cited for: VARIANT SER-2019;

Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics.
Kay D.M.; Zabetian C.P.; Factor S.A.; Nutt J.G.; Samii A.; Griffith A.; Bird T.D.; Kramer P.; Higgins D.S.; Payami H.;
Mov. Disord. 21:519-523(2006)
Cited for: VARIANT PARK8 SER-2019;

Lrrk2 pathogenic substitutions in Parkinson's disease.
Mata I.F.; Kachergus J.M.; Taylor J.P.; Lincoln S.; Aasly J.; Lynch T.; Hulihan M.M.; Cobb S.A.; Wu R.-M.; Lu C.-S.; Lahoz C.; Wszolek Z.K.; Farrer M.J.;
Neurogenetics 6:171-177(2005)
Cited for: VARIANTS PARK8 CYS-1441; GLY-1441; HIS-1441; GLN-1514; SER-1542; GLU-1598; CYS-1699; THR-1869; THR-2012; SER-2019; THR-2020 AND ARG-2385; VARIANTS PRO-119; LYS-551; VAL-723; MET-793; VAL-1122; ALA-1262; HIS-1398; PRO-1628; THR-1646; THR-1647; ASP-2081; LEU-2119; ILE-2261 AND THR-2397;

LRRK2 gene in Parkinson disease: mutation analysis and case control association study.
Paisan-Ruiz C.; Lang A.E.; Kawarai T.; Sato C.; Salehi-Rad S.; Fisman G.K.; Al-Khairallah T.; St George-Hyslop P.H.; Singleton A.; Rogaeva E.;
Neurology 65:696-700(2005)
Cited for: VARIANTS PARK8 VAL-1371 AND SER-2019; VARIANTS HIS-1398 AND THR-2397;

LRRK2 mutations in Parkinson disease.
Farrer M.; Stone J.; Mata I.F.; Lincoln S.; Kachergus J.; Hulihan M.; Strain K.J.; Maraganore D.M.;
Neurology 65:738-740(2005)
Cited for: VARIANTS PARK8 MET-793; THR-1869 AND SER-2019;

A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations.
Zabetian C.P.; Samii A.; Mosley A.D.; Roberts J.W.; Leis B.C.; Yearout D.; Raskind W.H.; Griffith A.;
Neurology 65:741-744(2005)
Cited for: VARIANTS PARK8 CYS-1441; HIS-1441 AND SER-2019;

LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease.
Infante J.; Rodriguez E.; Combarros O.; Mateo I.; Fontalba A.; Pascual J.; Oterino A.; Polo J.M.; Leno C.; Berciano J.;
Neurosci. Lett. 395:224-226(2006)
Cited for: VARIANT PARK8 SER-2019;

Clinical traits of LRRK2-associated Parkinson's disease in Ireland: a link between familial and idiopathic PD.
Gosal D.; Ross O.A.; Wiley J.; Irvine G.B.; Johnston J.A.; Toft M.; Mata I.F.; Kachergus J.; Hulihan M.; Taylor J.P.; Lincoln S.J.; Farrer M.J.; Lynch T.; Mark Gibson J.;
Parkinsonism Relat. Disord. 11:349-352(2005)
Cited for: VARIANT PARK8 SER-2019;

LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance.
Gaig C.; Ezquerra M.; Marti M.J.; Munoz E.; Valldeoriola F.; Tolosa E.;
Arch. Neurol. 63:377-382(2006)
Cited for: VARIANTS PARK8 CYS-1441; GLY-1441 AND SER-2019;

Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls.
Paisan-Ruiz C.; Nath P.; Washecka N.; Gibbs J.R.; Singleton A.B.;
Hum. Mutat. 29:485-490(2008)
Cited for: VARIANTS PARK8 VAL-712; LEU-1728; HIS-1728; SER-2019; MET-2141; HIS-2143 AND HIS-2466; VARIANTS SER-228; VAL-716; GLU-871; PHE-1870 AND LYS-2395;

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 PARK8 SER-2019;

Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
Cho H.J.; Yu J.; Xie C.; Rudrabhatla P.; Chen X.; Wu J.; Parisiadou L.; Liu G.; Sun L.; Ma B.; Ding J.; Liu Z.; Cai H.;
EMBO J. 33:2314-2331(2014)

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.