RBCC Red Blood Cell Collection

PARK7 [Confidence: low (only semi-automatic identification from reviews)]
Protein DJ-1; 3.4.-.- (Oncogene DJ1; Parkinson disease protein 7; Flags: Precursor)

UniProt Q99497
ID PARK7_HUMAN Reviewed; 189 AA.
AC Q99497; B2R4Z1; O14805; Q6DR95; Q7LFU2;
DT 07-DEC-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 2.
DT 22-JAN-2014, entry version 140.
DE RecName: Full=Protein DJ-1;
DE EC=3.4.-.-;
DE AltName: Full=Oncogene DJ1;
DE AltName: Full=Parkinson disease protein 7;
DE Flags: Precursor;
GN Name=PARK7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Cervix carcinoma;
RX PubMed=9070310; DOI=10.1006/bbrc.1997.6132;
RA Nagakubo D., Taita T., Kitaura H., Ikeda M., Tamai K.,
RA Iguchi-Ariga S.M.M., Ariga H.;
RT "DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in
RT cooperation with ras.";
RL Biochem. Biophys. Res. Commun. 231:509-513(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lung;
RA Beaudoin R., Hod Y.;
RT "Homo sapiens RNA-binding protein regulatory subunit mRNA.";
RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Ariga H., Niki T.;
RT "Human DJ-1 cDNA from PC3 cells.";
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cervix;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-6.
RC TISSUE=Kidney;
RX PubMed=11223268; DOI=10.1016/S0378-1119(00)00590-4;
RA Taira T., Takahashi K., Kitagawa R., Iguchi-Ariga S.M.M., Ariga H.;
RT "Molecular cloning of human and mouse DJ-1 genes and identification of
RT Sp1-dependent activation of the human DJ-1 promoter.";
RL Gene 263:285-292(2001).
RN [9]
RP PROTEIN SEQUENCE OF 6-27; 33-89; 99-122 AND 149-175, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 138-189, AND VARIANT SER-150.
RA Zou H.Q., Chan P.;
RT "DJ-1 gene G150S mutation.";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP INTERACTION WITH PIAS2, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=11477070; DOI=10.1074/jbc.M101730200;
RA Takahashi K., Taira T., Niki T., Seino C., Iguchi-Ariga S.M.M.,
RA Ariga H.;
RT "DJ-1 positively regulates the androgen receptor by impairing the
RT binding of PIASx alpha to the receptor.";
RL J. Biol. Chem. 276:37556-37563(2001).
RN [12]
RP DEGRADATION BY THE PROTEASOME, SUBCELLULAR LOCATION, INTERACTION WITH
RP PIAS2, HOMODIMERIZATION, MUTAGENESIS OF LYS-130, AND CHARACTERIZATION
RP OF VARIANT PARK7 PRO-166.
RX PubMed=12851414; DOI=10.1074/jbc.M304272200;
RA Miller D.W., Ahmad R., Hague S., Baptista M.J., Canet-Aviles R.,
RA McLendon C., Carter D.M., Zhu P.-P., Stadler J., Chandran J.,
RA Klinefelter G.R., Blackstone C., Cookson M.R.;
RT "L166P mutant DJ-1, causative for recessive Parkinson's disease, is
RT degraded through the ubiquitin-proteasome system.";
RL J. Biol. Chem. 278:36588-36595(2003).
RN [13]
RP DEGRADATION BY THE PROTEASOME, AND CHARACTERIZATION OF VARIANTS PARK7
RP ILE-26 AND PRO-166.
RX PubMed=14713311;
RA Moore D.J., Zhang L., Dawson T.M., Dawson V.L.;
RT "A missense mutation (L166P) in DJ-1, linked to familial Parkinson's
RT disease, confers reduced protein stability and impairs homo-
RT oligomerization.";
RL J. Neurochem. 87:1558-1567(2003).
RN [14]
RP INTERACTION WITH EFCAB6, AND FUNCTION.
RX PubMed=12612053;
RA Niki T., Takahashi-Niki K., Taira T., Iguchi-Ariga S.M.M., Ariga H.;
RT "DJBP: a novel DJ-1-binding protein, negatively regulates the androgen
RT receptor by recruiting histone deacetylase complex, and DJ-1
RT antagonizes this inhibition by abrogation of this complex.";
RL Mol. Cancer Res. 1:247-261(2003).
RN [15]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=14579415; DOI=10.1002/mrd.10360;
RA Yoshida K., Sato Y., Yoshiike M., Nozawa S., Ariga H., Iwamoto T.;
RT "Immunocytochemical localization of DJ-1 in human male reproductive
RT tissue.";
RL Mol. Reprod. Dev. 66:391-397(2003).
RN [16]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=14705119; DOI=10.1002/ana.10782;
RA Rizzu P., Hinkle D.A., Zhukareva V., Bonifati V., Severijnen L.-A.,
RA Martinez D., Ravid R., Kamphorst W., Eberwine J.H., Lee V.M.-Y.,
RA Trojanowski J.Q., Heutink P.;
RT "DJ-1 colocalizes with tau inclusions: a link between parkinsonism and
RT dementia.";
RL Ann. Neurol. 55:113-118(2004).
RN [17]
RP TISSUE SPECIFICITY.
RX PubMed=14662519; DOI=10.1093/brain/awh054;
RA Bandopadhyay R., Kingsbury A.E., Cookson M.R., Reid A.R., Evans I.M.,
RA Hope A.D., Pittman A.M., Lashley T., Canet-Aviles R., Miller D.W.,
RA McLendon C., Strand C., Leonard A.J., Abou-Sleiman P.M., Healy D.G.,
RA Ariga H., Wood N.W., de Silva R., Revesz T., Hardy J.A., Lees A.J.;
RT "The expression of DJ-1 (PARK7) in normal human CNS and idiopathic
RT Parkinson's disease.";
RL Brain 127:420-430(2004).
RN [18]
RP FUNCTION, INDUCTION, AND MUTAGENESIS OF VAL-51 AND CYS-53.
RX PubMed=14749723; DOI=10.1038/sj.embor.7400074;
RA Taira T., Saito Y., Niki T., Iguchi-Ariga S.M., Takahashi K.,
RA Ariga H.;
RT "DJ-1 has a role in antioxidative stress to prevent cell death.";
RL EMBO Rep. 5:213-218(2004).
RN [19]
RP FUNCTION, AND MUTAGENESIS OF CYS-46; CYS-53 AND CYS-106.
RX PubMed=15502874; DOI=10.1371/journal.pbio.0020362;
RA Shendelman S., Jonason A., Martinat C., Leete T., Abeliovich A.;
RT "DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-
RT synuclein aggregate formation.";
RL PLoS Biol. 2:1-10(2004).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-67, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [21]
RP SUMOYLATION AT LYS-130, OXIDATION, SUBCELLULAR LOCATION, INDUCTION,
RP AND FUNCTION.
RX PubMed=15976810; DOI=10.1038/sj.cdd.4401704;
RA Shinbo Y., Niki T., Taira T., Ooe H., Takahashi-Niki K., Maita C.,
RA Seino C., Iguchi-Ariga S.M.M., Ariga H.;
RT "Proper SUMO-1 conjugation is essential to DJ-1 to exert its full
RT activities.";
RL Cell Death Differ. 13:96-108(2006).
RN [22]
RP FUNCTION, INTERACTION WITH HIPK1, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF CYS-106.
RX PubMed=16390825; DOI=10.1080/10715760500456847;
RA Sekito A., Koide-Yoshida S., Niki T., Taira T., Iguchi-Ariga S.M.M.,
RA Ariga H.;
RT "DJ-1 interacts with HIPK1 and affects H2O2-induced cell death.";
RL Free Radic. Res. 40:155-165(2006).
RN [23]
RP FUNCTION.
RX PubMed=17015834; DOI=10.1073/pnas.0607260103;
RA Clements C.M., McNally R.S., Conti B.J., Mak T.W., Ting J.P.;
RT "DJ-1, a cancer- and Parkinson's disease-associated protein,
RT stabilizes the antioxidant transcriptional master regulator Nrf2.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15091-15096(2006).
RN [24]
RP FUNCTION.
RX PubMed=18626009; DOI=10.1073/pnas.0708518105;
RA van der Brug M.P., Blackinton J., Chandran J., Hao L.Y., Lal A.,
RA Mazan-Mamczarz K., Martindale J., Xie C., Ahmad R., Thomas K.J.,
RA Beilina A., Gibbs J.R., Ding J., Myers A.J., Zhan M., Cai H.,
RA Bonini N.M., Gorospe M., Cookson M.R.;
RT "RNA binding activity of the recessive parkinsonism protein DJ-1
RT supports involvement in multiple cellular pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10244-10249(2008).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-46; CYS-53 AND
RP CYS-106.
RX PubMed=18711745; DOI=10.1002/jnr.21831;
RA Junn E., Jang W.H., Zhao X., Jeong B.S., Mouradian M.M.;
RT "Mitochondrial localization of DJ-1 leads to enhanced
RT neuroprotection.";
RL J. Neurosci. Res. 87:123-129(2009).
RN [26]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVE SITES, AND MUTAGENESIS
RP OF CYS-106 AND HIS-126.
RX PubMed=20304780; DOI=10.1093/hmg/ddq113;
RA Chen J., Li L., Chin L.S.;
RT "Parkinson disease protein DJ-1 converts from a zymogen to a protease
RT by carboxyl-terminal cleavage.";
RL Hum. Mol. Genet. 19:2395-2408(2010).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [28]
RP FUNCTION, INTERACTION WITH BBS1; CLCF1; MTERF AND OTUD7B, AND
RP MUTAGENESIS OF CYS-106.
RX PubMed=21097510; DOI=10.1074/jbc.M110.147371;
RA McNally R.S., Davis B.K., Clements C.M., Accavitti-Loper M.A.,
RA Mak T.W., Ting J.P.;
RT "DJ-1 enhances cell survival through the binding of cezanne, a
RT negative regulator of NF-{kappa}B.";
RL J. Biol. Chem. 286:4098-4106(2011).
RN [29]
RP FUNCTION, PALMITOYLATION AT CYS-46; CYS-53 AND CYS-106, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF CYS-46; CYS-106 AND LEU-166.
RX PubMed=23847046; DOI=10.1093/hmg/ddt332;
RA Kim K.S., Kim J.S., Park J.Y., Suh Y.H., Jou I., Joe E.H., Park S.M.;
RT "DJ-1 associates with lipid rafts by palmitoylation and regulates
RT lipid rafts-dependent endocytosis in astrocytes.";
RL Hum. Mol. Genet. 22:4805-4817(2013).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS), AND HOMODIMERIZATION.
RX PubMed=12914946; DOI=10.1016/S0014-5793(03)00764-6;
RA Huai Q., Sun Y., Wang H., Chin L.-S., Li L., Robinson H., Ke H.;
RT "Crystal structure of DJ-1/RS and implication on familial Parkinson's
RT disease.";
RL FEBS Lett. 549:171-175(2003).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF WILD-TYPE AND MUTANT ARG-130,
RP AND HOMODIMERIZATION.
RX PubMed=12761214; DOI=10.1074/jbc.M304221200;
RA Tao X., Tong L.;
RT "Crystal structure of human DJ-1, a protein associated with early
RT onset Parkinson's disease.";
RL J. Biol. Chem. 278:31372-31379(2003).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS), AND HOMODIMERIZATION.
RX PubMed=12796482; DOI=10.1074/jbc.M305878200;
RA Honbou K., Suzuki N.N., Horiuchi M., Niki T., Taira T., Ariga H.,
RA Inagaki F.;
RT "The crystal structure of DJ-1, a protein related to male fertility
RT and Parkinson's disease.";
RL J. Biol. Chem. 278:31380-31384(2003).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), FUNCTION, OXIDATION, AND
RP HOMODIMERIZATION.
RX PubMed=12939276; DOI=10.1074/jbc.M304517200;
RA Lee S.-J., Kim S.J., Kim I.-K., Ko J., Jeong C.-S., Kim G.-H.,
RA Park C., Kang S.-O., Suh P.-G., Lee H.-S., Cha S.-S.;
RT "Crystal structures of human DJ-1 and Escherichia coli Hsp31, which
RT share an evolutionarily conserved domain.";
RL J. Biol. Chem. 278:44552-44559(2003).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS), HOMODIMERIZATION, OXIDATION,
RP AND LACK OF PROTEOLYTIC ACTIVITY.
RX PubMed=12855764; DOI=10.1073/pnas.1133288100;
RA Wilson M.A., Collins J.L., Hod Y., Ringe D., Petsko G.A.;
RT "The 1.1-A resolution crystal structure of DJ-1, the protein mutated
RT in autosomal recessive early onset Parkinson's disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:9256-9261(2003).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS), MUTAGENESIS OF CYS-46; CYS-53
RP AND CYS-106, OXIDATION, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15181200; DOI=10.1073/pnas.0402959101;
RA Canet-Aviles R.M., Wilson M.A., Miller D.W., Ahmad R., McLendon C.,
RA Bandyopadhyay S., Baptista M.J., Ringe D., Petsko G.A., Cookson M.R.;
RT "The Parkinson's disease protein DJ-1 is neuroprotective due to
RT cysteine-sulfinic acid-driven mitochondrial localization.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:9103-9108(2004).
RN [36]
RP VARIANTS PARK7 ILE-26 AND ALA-149, AND VARIANT GLN-98.
RX PubMed=12953260; DOI=10.1002/ana.10675;
RA Abou-Sleiman P.M., Healy D.G., Quinn N., Lees A.J., Wood N.W.;
RT "The role of pathogenic DJ-1 mutations in Parkinson's disease.";
RL Ann. Neurol. 54:283-286(2003).
RN [37]
RP VARIANT PARK7 PRO-166, AND SUBCELLULAR LOCATION.
RX PubMed=12446870; DOI=10.1126/science.1077209;
RA Bonifati V., Rizzu P., van Baren M.J., Schaap O., Breedveld G.J.,
RA Krieger E., Dekker M.C.J., Squitieri F., Ibanez P., Joosse M.,
RA van Dongen J.W., Vanacore N., van Swieten J.C., Brice A., Meco G.,
RA van Duijn C.M., Oostra B.A., Heutink P.;
RT "Mutations in the DJ-1 gene associated with autosomal recessive early-
RT onset Parkinsonism.";
RL Science 299:256-259(2003).
RN [38]
RP VARIANT GLN-98.
RX PubMed=14705128; DOI=10.1002/ana.10816;
RA Hedrich K., Schaefer N., Hering R., Hagenah J., Lanthaler A.J.,
RA Schwinger E., Kramer P.L., Ozelius L.J., Bressman S.B., Abbruzzese G.,
RA Martinelli P., Kostic V., Pramstaller P.P., Vieregge P., Riess O.,
RA Klein C.;
RT "The R98Q variation in DJ-1 represents a rare polymorphism.";
RL Ann. Neurol. 55:145-146(2004).
RN [39]
RP VARIANT PARK7 ASP-64, AND X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=15365989; DOI=10.1002/humu.20089;
RA Hering R., Strauss K.M., Tao X., Bauer A., Woitalla D., Mietz E.M.,
RA Petrovic S., Bauer P., Schaible W., Mueller T., Schoels L., Klein C.,
RA Berg D., Meyer P.T., Schulz J.B., Wollnik B., Tong L., Krueger R.,
RA Riess O.;
RT "Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson
RT disease (PARK7).";
RL Hum. Mutat. 24:321-329(2004).
RN [40]
RP CHARACTERIZATION OF VARIANTS PARK7 ASP-64 AND PRO-166.
RX PubMed=14607841; DOI=10.1074/jbc.M309204200;
RA Goerner K., Holtorf E., Odoy S., Nuscher B., Yamamoto A., Regula J.T.,
RA Beyer K., Haass C., Kahle P.J.;
RT "Differential effects of Parkinson's disease-associated mutations on
RT stability and folding of DJ-1.";
RL J. Biol. Chem. 279:6943-6951(2004).
RN [41]
RP VARIANT PARK7 THR-104, AND VARIANTS GLN-98 AND SER-171.
RX PubMed=15254937; DOI=10.1002/mds.20131;
RA Clark L.N., Afridi S., Mejia-Santana H., Harris J., Louis E.D.,
RA Cote L.J., Andrews H., Singleton A., Wavrant De-Vrieze F., Hardy J.,
RA Mayeux R., Fahn S., Waters C., Ford B., Frucht S., Ottman R.,
RA Marder K.;
RT "Analysis of an early-onset Parkinson's disease cohort for DJ-1
RT mutations.";
RL Mov. Disord. 19:796-800(2004).
RN [42]
RP VARIANT GLN-98.
RX PubMed=14872018;
RA Hedrich K., Djarmati A., Schafer N., Hering R., Wellenbrock C.,
RA Weiss P.H., Hilker R., Vieregge P., Ozelius L.J., Heutink P.,
RA Bonifati V., Schwinger E., Lang A.E., Noth J., Bressman S.B.,
RA Pramstaller P.P., Riess O., Klein C.;
RT "DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2)
RT mutations in early-onset Parkinson disease.";
RL Neurology 62:389-394(2004).
RN [43]
RP VARIANT LYS-163.
RX PubMed=16240358; DOI=10.1002/ana.20666;
RA Annesi G., Savettieri G., Pugliese P., D'Amelio M., Tarantino P.,
RA Ragonese P., La Bella V., Piccoli T., Civitelli D., Annesi F.,
RA Fierro B., Piccoli F., Arabia G., Caracciolo M., Ciro Candiano I.C.,
RA Quattrone A.;
RT "DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral
RT sclerosis complex.";
RL Ann. Neurol. 58:803-807(2005).
RN [44]
RP CHARACTERIZATION OF VARIANT PARK7 PRO-166.
RX PubMed=17846173; DOI=10.1083/jcb.200611128;
RA Olzmann J.A., Li L., Chudaev M.V., Chen J., Perez F.A., Palmiter R.D.,
RA Chin L.S.;
RT "Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1
RT to aggresomes via binding to HDAC6.";
RL J. Cell Biol. 178:1025-1038(2007).
RN [45]
RP VARIANT ASP-64.
RX PubMed=20186336; DOI=10.1371/journal.pone.0009367;
RA Krebiehl G., Ruckerbauer S., Burbulla L.F., Kieper N., Maurer B.,
RA Waak J., Wolburg H., Gizatullina Z., Gellerich F.N., Woitalla D.,
RA Riess O., Kahle P.J., Proikas-Cezanne T., Kruger R.;
RT "Reduced basal autophagy and impaired mitochondrial dynamics due to
RT loss of Parkinson's disease-associated protein DJ-1.";
RL PLoS ONE 5:E9367-E9367(2010).
CC -!- FUNCTION: Protects cells against oxidative stress and cell death.
CC Plays a role in regulating expression or stability of the
CC mitochondrial uncoupling proteins SLC25A14 and SLC25A27 in
CC dopaminergic neurons of the substantia nigra pars compacta and
CC attenuates the oxidative stress induced by calcium entry into the
CC neurons via L-type channels during pacemaking. Eliminates hydrogen
CC peroxide and protects cells against hydrogen peroxide-induced cell
CC death. May act as an atypical peroxiredoxin-like peroxidase that
CC scavenges hydrogen peroxide. Following removal of a C-terminal
CC peptide, displays protease activity and enhanced cytoprotective
CC action against oxidative stress-induced apoptosis. Stabilizes
CC NFE2L2 by preventing its association with KEAP1 and its subsequent
CC ubiquitination. Binds to OTUD7B and inhibits its deubiquitinating
CC activity. Enhances RELA nuclear translocation. Binds to a number
CC of mRNAs containing multiple copies of GG or CC motifs and
CC partially inhibits their translation but dissociates following
CC oxidative stress. Required for correct mitochondrial morphology
CC and function and for autophagy of dysfunctional mitochondria.
CC Regulates astrocyte inflammatory responses. Acts as a positive
CC regulator of androgen receptor-dependent transcription. Prevents
CC aggregation of SNCA. Plays a role in fertilization. Has no
CC proteolytic activity. Has cell-growth promoting activity and
CC transforming activity. May function as a redox-sensitive
CC chaperone. May regulate lipid rafts-dependent endocytosis in
CC astrocytes and neuronal cells.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=173.4 uM for casein;
CC -!- SUBUNIT: Homodimer. Binds EFCAB6/DJBP and PIAS2. Part of a ternary
CC complex containing PARK7, EFCAB6/DJBP and AR. Interacts (via N-
CC terminus) with OTUD7B. Interacts with BBS1, HIPK1, CLCF1 and
CC MTERF.
CC -!- INTERACTION:
CC P10275:AR; NbExp=6; IntAct=EBI-1164361, EBI-608057;
CC Q9UER7:DAXX; NbExp=3; IntAct=EBI-1164361, EBI-77321;
CC Q13158:FADD; NbExp=9; IntAct=EBI-1164361, EBI-494804;
CC O94776:MTA2; NbExp=3; IntAct=EBI-1164361, EBI-1783035;
CC Q6GQQ9:OTUD7B; NbExp=3; IntAct=EBI-1164361, EBI-527784;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor. Cytoplasm.
CC Nucleus. Membrane raft. Mitochondrion. Note=Under normal
CC conditions, located predominantly in the cytoplasm and, to a
CC lesser extent, in the nucleus and mitochondrion. Translocates to
CC the mitochondrion and subsequently to the nucleus in response to
CC oxidative stress and exerts an increased cytoprotective effect
CC against oxidative damage. Detected in tau inclusions in brains
CC from neurodegenerative disease patients. Membrane raft
CC localization in astrocytes and neuronal cells requires
CC palmitoylation.
CC -!- TISSUE SPECIFICITY: Highly expressed in pancreas, kidney, skeletal
CC muscle, liver, testis and heart. Detected at slightly lower levels
CC in placenta and brain. Detected in astrocytes, Sertoli cells,
CC spermatogonia, spermatids and spermatozoa.
CC -!- INDUCTION: By hydrogen peroxide and UV irradiation.
CC -!- PTM: Sumoylated on Lys-130 by PIAS2 or PIAS4; which is enhanced
CC after ultraviolet irradiation and essential for cell-growth
CC promoting activity and transforming activity.
CC -!- PTM: Cys-106 is easily oxidized to sulfinic acid.
CC -!- PTM: Undergoes cleavage of a C-terminal peptide and subsequent
CC activation of protease activity in response to oxidative stress.
CC -!- DISEASE: Parkinson disease 7 (PARK7) [MIM:606324]: A
CC neurodegenerative disorder characterized by resting tremor,
CC postural tremor, bradykinesia, muscular rigidity, anxiety and
CC psychotic episodes. PARK7 has onset before 40 years, slow
CC progression and initial good response to levodopa. Some patients
CC may show traits reminiscent of amyotrophic lateral sclerosis-
CC parkinsonism/dementia complex (Guam disease). Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C56 family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PARK7";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=P&genename;=PARK7+%40+DJ-1";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; D61380; BAA09603.2; -; mRNA.
DR EMBL; AF021819; AAC12806.1; -; mRNA.
DR EMBL; AB073864; BAB71782.1; -; mRNA.
DR EMBL; AK312000; BAG34938.1; -; mRNA.
DR EMBL; AL034417; CAB52550.1; -; Genomic_DNA.
DR EMBL; CH471130; EAW71591.1; -; Genomic_DNA.
DR EMBL; BC008188; AAH08188.1; -; mRNA.
DR EMBL; AB045294; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AY648999; AAT68961.1; -; Genomic_DNA.
DR PIR; JC5394; JC5394.
DR RefSeq; NP_001116849.1; NM_001123377.1.
DR RefSeq; NP_009193.2; NM_007262.4.
DR RefSeq; XP_005263481.1; XM_005263424.1.
DR UniGene; Hs.419640; -.
DR PDB; 1J42; X-ray; 2.50 A; A=1-189.
DR PDB; 1P5F; X-ray; 1.10 A; A=1-189.
DR PDB; 1PDV; X-ray; 1.80 A; A=1-189.
DR PDB; 1PDW; X-ray; 2.20 A; A/B/C/D/E/F/G/H=1-189.
DR PDB; 1PE0; X-ray; 1.70 A; A/B=1-189.
DR PDB; 1Q2U; X-ray; 1.60 A; A=1-189.
DR PDB; 1SOA; X-ray; 1.20 A; A=1-189.
DR PDB; 1UCF; X-ray; 1.95 A; A/B=1-189.
DR PDB; 2OR3; X-ray; 1.20 A; A/B=1-189.
DR PDB; 2R1T; X-ray; 1.70 A; A/B=2-188.
DR PDB; 2R1U; X-ray; 1.50 A; A/B=2-188.
DR PDB; 2R1V; X-ray; 1.70 A; A/B=2-188.
DR PDB; 2RK3; X-ray; 1.05 A; A=1-189.
DR PDB; 2RK4; X-ray; 1.15 A; A=1-189.
DR PDB; 2RK6; X-ray; 1.15 A; A=1-189.
DR PDB; 3B36; X-ray; 1.50 A; A=1-189.
DR PDB; 3B38; X-ray; 1.85 A; A=1-189.
DR PDB; 3B3A; X-ray; 1.50 A; A=1-189.
DR PDB; 3BWE; X-ray; 2.40 A; A/B/C/D/E/F/G=1-189.
DR PDB; 3CY6; X-ray; 1.35 A; A=1-189.
DR PDB; 3CYF; X-ray; 1.60 A; A=1-189.
DR PDB; 3CZ9; X-ray; 1.15 A; A=1-189.
DR PDB; 3CZA; X-ray; 1.20 A; A=1-189.
DR PDB; 3EZG; X-ray; 1.15 A; A=1-189.
DR PDB; 3F71; X-ray; 1.20 A; A=1-189.
DR PDB; 3SF8; X-ray; 1.56 A; A/B=1-189.
DR PDB; 4BTE; X-ray; 1.38 A; A=1-189.
DR PDBsum; 1J42; -.
DR PDBsum; 1P5F; -.
DR PDBsum; 1PDV; -.
DR PDBsum; 1PDW; -.
DR PDBsum; 1PE0; -.
DR PDBsum; 1Q2U; -.
DR PDBsum; 1SOA; -.
DR PDBsum; 1UCF; -.
DR PDBsum; 2OR3; -.
DR PDBsum; 2R1T; -.
DR PDBsum; 2R1U; -.
DR PDBsum; 2R1V; -.
DR PDBsum; 2RK3; -.
DR PDBsum; 2RK4; -.
DR PDBsum; 2RK6; -.
DR PDBsum; 3B36; -.
DR PDBsum; 3B38; -.
DR PDBsum; 3B3A; -.
DR PDBsum; 3BWE; -.
DR PDBsum; 3CY6; -.
DR PDBsum; 3CYF; -.
DR PDBsum; 3CZ9; -.
DR PDBsum; 3CZA; -.
DR PDBsum; 3EZG; -.
DR PDBsum; 3F71; -.
DR PDBsum; 3SF8; -.
DR PDBsum; 4BTE; -.
DR ProteinModelPortal; Q99497; -.
DR SMR; Q99497; 3-188.
DR DIP; DIP-35515N; -.
DR IntAct; Q99497; 31.
DR MINT; MINT-5003468; -.
DR STRING; 9606.ENSP00000340278; -.
DR MEROPS; C56.002; -.
DR PhosphoSite; Q99497; -.
DR DMDM; 56404943; -.
DR OGP; Q99497; -.
DR REPRODUCTION-2DPAGE; IPI00298547; -.
DR UCD-2DPAGE; O14805; -.
DR UCD-2DPAGE; Q99497; -.
DR PaxDb; Q99497; -.
DR PeptideAtlas; Q99497; -.
DR PRIDE; Q99497; -.
DR DNASU; 11315; -.
DR Ensembl; ENST00000338639; ENSP00000340278; ENSG00000116288.
DR Ensembl; ENST00000377488; ENSP00000366708; ENSG00000116288.
DR Ensembl; ENST00000377491; ENSP00000366711; ENSG00000116288.
DR Ensembl; ENST00000493373; ENSP00000465404; ENSG00000116288.
DR Ensembl; ENST00000493678; ENSP00000418770; ENSG00000116288.
DR GeneID; 11315; -.
DR KEGG; hsa:11315; -.
DR UCSC; uc001aou.4; human.
DR CTD; 11315; -.
DR GeneCards; GC01P008014; -.
DR HGNC; HGNC:16369; PARK7.
DR HPA; CAB005870; -.
DR HPA; HPA004190; -.
DR MIM; 168600; phenotype.
DR MIM; 602533; gene.
DR MIM; 606324; phenotype.
DR neXtProt; NX_Q99497; -.
DR Orphanet; 90020; Amyotrophic lateral sclerosis-parkinsonism-dementia complex.
DR Orphanet; 2828; Young adult-onset Parkinsonism.
DR PharmGKB; PA32946; -.
DR eggNOG; COG0693; -.
DR HOGENOM; HOG000063194; -.
DR HOVERGEN; HBG053511; -.
DR InParanoid; Q99497; -.
DR KO; K05687; -.
DR OMA; ATCYPGF; -.
DR OrthoDB; EOG7CVPZX; -.
DR PhylomeDB; Q99497; -.
DR SignaLink; Q99497; -.
DR EvolutionaryTrace; Q99497; -.
DR GeneWiki; PARK7; -.
DR GenomeRNAi; 11315; -.
DR NextBio; 42983; -.
DR PMAP-CutDB; Q99497; -.
DR PRO; PR:Q99497; -.
DR ArrayExpress; Q99497; -.
DR Bgee; Q99497; -.
DR CleanEx; HS_PARK7; -.
DR Genevestigator; Q99497; -.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; IDA:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0004601; F:peroxidase activity; ISS:UniProtKB.
DR GO; GO:0051920; F:peroxiredoxin activity; IEA:Ensembl.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:UniProtKB.
DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IEA:Ensembl.
DR GO; GO:0042743; P:hydrogen peroxide metabolic process; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0051899; P:membrane depolarization; IEA:Ensembl.
DR GO; GO:0060081; P:membrane hyperpolarization; IEA:Ensembl.
DR GO; GO:0007005; P:mitochondrion organization; ISS:UniProtKB.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:BHF-UCL.
DR GO; GO:0032091; P:negative regulation of protein binding; IDA:UniProtKB.
DR GO; GO:2000277; P:positive regulation of oxidative phosphorylation uncoupler activity; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0060765; P:regulation of androgen receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0007338; P:single fertilization; IEA:UniProtKB-KW.
DR InterPro; IPR006287; DJ1.
DR InterPro; IPR002818; ThiJ/PfpI.
DR Pfam; PF01965; DJ-1_PfpI; 1.
DR TIGRFAMs; TIGR01383; not_thiJ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Autophagy; Cell membrane; Chaperone; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation; Fertilization;
KW Hydrolase; Inflammatory response; Isopeptide bond; Lipoprotein;
KW Membrane; Mitochondrion; Neurodegeneration; Nucleus; Oxidation;
KW Palmitate; Parkinson disease; Parkinsonism; Phosphoprotein;
KW Polymorphism; Protease; Reference proteome; RNA-binding;
KW Stress response; Tumor suppressor; Ubl conjugation; Zymogen.
FT CHAIN 1 ? Protein DJ-1.
FT /FTId=PRO_0000157849.
FT PROPEP ? 189 Removed in mature form.
FT /FTId=PRO_0000405558.
FT ACT_SITE 106 106 Probable.
FT ACT_SITE 126 126 Probable.
FT MOD_RES 67 67 Phosphotyrosine.
FT MOD_RES 106 106 Cysteine sulfinic acid (-SO2H).
FT LIPID 46 46 S-palmitoyl cysteine.
FT LIPID 53 53 S-palmitoyl cysteine.
FT LIPID 106 106 S-palmitoyl cysteine.
FT CROSSLNK 130 130 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT VARIANT 26 26 M -> I (in PARK7; does not affect protein
FT stability and degradation; does not
FT interfere with homodimerization).
FT /FTId=VAR_020492.
FT VARIANT 64 64 E -> D (in PARK7; no apparent effect on
FT protein stability; impaired mitochondrial
FT morphology).
FT /FTId=VAR_020493.
FT VARIANT 98 98 R -> Q (in dbSNP:rs71653619).
FT /FTId=VAR_020494.
FT VARIANT 104 104 A -> T (in PARK7).
FT /FTId=VAR_020495.
FT VARIANT 149 149 D -> A (in PARK7; dbSNP:rs74315352).
FT /FTId=VAR_020496.
FT VARIANT 150 150 G -> S.
FT /FTId=VAR_020497.
FT VARIANT 163 163 E -> K.
FT /FTId=VAR_034801.
FT VARIANT 166 166 L -> P (in PARK7; reduces protein
FT stability and leads to increased
FT degradation; interferes with
FT homodimerization; abolishes interaction
FT with PIAS2; strongly reduces chaperone
FT activity; ubiquitinated by PARK2, leading
FT to its recognition by HDAC6 and targeting
FT to aggresome where is degraded;
FT dbSNP:rs28938172).
FT /FTId=VAR_020498.
FT VARIANT 171 171 A -> S.
FT /FTId=VAR_020499.
FT MUTAGEN 46 46 C->A: Reduced localization in lipid
FT rafts; when associated with A-106.
FT MUTAGEN 46 46 C->A: Reduces protein stability. No
FT effect on oxidation.
FT MUTAGEN 46 46 C->S: No effect on mitochondrial
FT translocation.
FT MUTAGEN 51 51 V->A: Disrupts dimer formation and
FT strongly reduces ability to eliminate
FT hydrogen peroxide.
FT MUTAGEN 53 53 C->A: Strongly reduces chaperone activity
FT and ability to eliminate hydrogen
FT peroxide.
FT MUTAGEN 53 53 C->S: No effect on mitochondrial
FT translocation.
FT MUTAGEN 106 106 C->A: Abolishes oxidation, association
FT with mitochondria and protease activity.
FT No effect on chaperone activity. Reduced
FT binding to OTUD7B.
FT MUTAGEN 106 106 C->A: Reduced localization in lipid
FT rafts; when associated with A-46.
FT MUTAGEN 106 106 C->D: Abolishes oxidation and association
FT with mitochondria. No effect on chaperone
FT activity.
FT MUTAGEN 106 106 C->S: No effect on mitochondrial
FT translocation. Reduced protease activity.
FT MUTAGEN 126 126 H->A: Abolishes protease activity.
FT MUTAGEN 130 130 K->R: Partially compensates for loss of
FT stability; when associated with P-166.
FT MUTAGEN 166 166 L->P: Reduced localization in lipid
FT rafts.
FT CONFLICT 119 119 F -> C (in Ref. 3; BAB71782).
FT STRAND 5 10
FT HELIX 16 28
FT STRAND 32 37
FT TURN 38 41
FT STRAND 51 53
FT STRAND 55 57
FT HELIX 58 62
FT STRAND 68 72
FT HELIX 76 84
FT HELIX 86 97
FT STRAND 101 105
FT TURN 106 108
FT HELIX 109 114
FT HELIX 127 129
FT HELIX 130 133
FT TURN 134 136
FT STRAND 139 141
FT STRAND 145 149
FT STRAND 152 155
FT HELIX 158 160
FT HELIX 161 173
FT HELIX 175 182
FT HELIX 183 185
SQ SEQUENCE 189 AA; 19891 MW; 4B21661B3A76BC67 CRC64;
MASKRALVIL AKGAEEMETV IPVDVMRRAG IKVTVAGLAG KDPVQCSRDV VICPDASLED
AKKEGPYDVV VLPGGNLGAQ NLSESAAVKE ILKEQENRKG LIAAICAGPT ALLAHEIGFG
SKVTTHPLAK DKMMNGGHYT YSENRVEKDG LILTSRGPGT SFEFALAIVE ALNGKEVAAQ
VKAPLVLKD
//

MIM 168600
*RECORD*
*FIELD* NO
168600
*FIELD* TI
#168600 PARKINSON DISEASE, LATE-ONSET; PD
;;PARK
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morelate-onset or sporadic Parkinson disease (PD) can have more than one
genetic and/or environmental cause.

DESCRIPTION

Parkinson disease was first described by James Parkinson in 1817. It is
the second most common neurodegenerative disorder after Alzheimer
disease (AD; 104300), affecting approximately 1% of the population over
age 50 (Polymeropoulos et al., 1996).

- Reviews

Warner and Schapira (2003) reviewed the genetic and environmental causes
of Parkinson disease. Feany (2004) reviewed the genetics of Parkinson
disease and provided a speculative model of interactions among proteins
implicated in PD. Lees et al. (2009) provided a review of Parkinson
disease, with emphasis on diagnosis, neuropathology, and treatment.

- Genetic Heterogeneity of Parkinson Disease

Several gene loci implicated in autosomal dominant forms of Parkinson
disease have been identified, including PARK1 (168601) and PARK4, due to
mutation in or triplication of the alpha-synuclein gene (SNCA; 163890),
respectively, on 4q22.1; PARK5 (191342), due to mutation in the UCHL1
gene on 4p14; PARK8 (607060), due to mutation in the LRRK2 gene (609007)
on 12q12; PARK11 (607688), due to mutation in the GIGYF2 gene (612003)
on 2q37; and PARK13 (610297), due to mutation in the HTRA2 gene (606441)
on 2p12. PARK17 (614203) is caused by mutation in the VPS35 gene
(601501) on chromosome 16q12, and PARK18 (614251) is caused by mutation
in the EIF4G1 gene (600495) on chromosome 3q27.

Several loci for autosomal recessive early-onset Parkinson disease have
been identified: PARK2 (600116), caused by mutation in the gene encoding
parkin (PARK2; 602544) on 6q25.2-q27; PARK6 (605909), caused by mutation
in the PINK1 gene (608309) on 1p36; PARK7 (606324), caused by mutation
in the DJ1 gene (PARK7; 602533) on 1p36; PARK14 (612953), caused by
mutation in the PLA2G6 gene (603604) on 22q13; PARK15 (260300), caused
by mutation in the FBXO7 gene (605648) on 22q12-q13; PARK19 (615528),
caused by mutation in the DNAJC6 gene (608375) on 1p32; and PARK20
(615530), caused by mutation in the SYNJ1 gene (604297) on 21q22.

PARK3 (602404) has been mapped to chromosome 2p13; PARK10 (606852) has
been mapped to chromosome 1p34-p32; PARK16 (613164) has been mapped to
chromosome 1q32. A locus on the X chromosome has been identified
(PARK12; 300557). There is also evidence that mitochondrial mutations
may cause or contribute to Parkinson disease (see 556500).

Susceptibility to the development of the more common late-onset form of
Parkinson disease has been associated with polymorphisms or mutations in
several genes, including GBA (606463), MAPT (157140), MC1R (155555),
ADH1C (103730), and genes at the HLA locus (see, e.g., HLA-DRA, 142860).
Each of these risk factors independently may have a modest effect on
disease development, but together may have a substantial cumulative
effect (Hamza et al., 2010).

Susceptibility to PD may also be conferred by expanded trinucleotide
repeats in several genes causing other neurologic disorders usually
characterized by spinocerebellar ataxia (SCA), including the ATXN2
(601517), ATXN3 (607047), TBP (600075), and ATXN8OS (603680) genes.

CLINICAL FEATURES

The diagnosis of classic idiopathic PD is primarily clinical, with
manifestations including resting tremor, muscular rigidity,
bradykinesia, and postural instability. Additional features are
characteristic postural abnormalities, dysautonomia, dystonic cramps,
and dementia. The disease is progressive and usually has an insidious
onset in mid to late adulthood. Pathologic features of classic PD
include by a loss of dopaminergic neurons in the substantia nigra (SN)
and the presence of Lewy bodies, intracellular inclusions, in surviving
neurons in various areas of the brain, particularly the SN (Nussbaum and
Polymeropoulos, 1997). Autosomal recessive juvenile Parkinson disease
(PARK2; 600116), however, does not have Lewy body pathology (Nussbaum
and Polymeropoulos, 1997).

Many other diseases, both genetic and nongenetic, have parkinsonian
motor features ('parkinsonism'), which most likely result from loss or
dysfunction of the dopaminergic neurons in the SN, but may or may not
have Lewy bodies on pathology. Thus, accurate diagnosis may be difficult
without pathologic examination. Dementia with Lewy bodies (DLB; 127750)
shows parkinsonism with Lewy bodies. However, parkinsonism without Lewy
bodies characterizes progressive supranuclear palsy (PSP; 601104),
frontotemporal dementia with parkinsonism (600274), autosomal dominant
(128230) and recessive (605407) forms of Segawa syndrome, X-linked
recessive Filipino type of dystonia (314250), multiple systems atrophy,
and cerebrovascular disease.

OTHER FEATURES

In a retrospective analysis, Paleacu et al. (2005) found that 76 (32%)
of 234 PD patients reported hallucinations. All experienced visual
hallucinations, most commonly of human images, and 6 also reported mood
congruent auditory hallucinations. The presence of hallucinations was
correlated with family history of dementia and lower scores on the
Mini-Mental State Examination (MMSE). Neither the dose nor duration of
L-dopa treatment was a significant variable for hallucinations.

Using PET scan, Ballanger et al. (2010) showed that 7 PD patients with
visual hallucinations had increased binding to serotonin 2A receptors
(HTR2A; 182135) in the ventral visual pathway compared to 7 PD patients
without visual hallucinations. Areas of the ventral visual pathway that
showed increased HTR2A binding included the bilateral inferooccipital
gyrus, the right fusiform gyrus, and the inferotemporal cortex. The
findings suggested that abnormalities in serotonin 2A receptor
neurotransmission may be involved in the pathogenesis of visual
hallucinations in PD.

Using single-photon emission CT with a radiolabeled ligand for several
beta-2 (CHRNB2; 118507)-containing nicotinic acetylcholine receptors
(nAChR), Fujita et al. (2006) showed that 10 nondemented PD patients had
a widespread significant global decrease in nAChRs compared to 15
controls. The most significant decrease was in the thalamus.

Some studies have observed an increased risk of Parkinson disease among
individuals with melanoma (155600) (see, e.g., Constantinescu et al.,
2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism
may be involved in the pathogenesis of PD. From 2 existing study cohorts
of 38,641 men and 93,661 women who were free of PD at baseline, Gao et
al. (2009) found an association between decreasing darkness of natural
hair color in early adulthood and increased PD risk. The pooled relative
risks (RR) for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for
black, brown, blond, and red hair, respectively. These results were
significant after adjusting for age, smoking, ethnicity, and other
covariates. The associations between hair color and PD were particularly
strong for onset before age 70 years. In a case-control study of 272 PD
cases and 1,185 controls, there was an association between the cys151
SNP of the MCR1 gene (155555.0004), which confers red hair, and
increased risk of PD relative to the arg151 SNP (relative risk of 3.15
for the cys/cys genotype). Noting that melanin, like dopamine, is
synthesized from tyrosine, and that PD is characterized by the loss of
neuromelanin-containing neurons in the substantia nigra, Gao et al.
(2009) postulated a link between pigmentation and development of PD.
Hernandez (2009) independently noted the association.

In a study of 157,036 individuals, who did not have PD at baseline, over
a 14 to 20-year follow-up period, Gao et al. (2009) identified 616
incident PD cases. A family history of melanoma in a first-degree
relative was associated with a higher risk of PD (RR, 1.85; p = 0.004)
after adjusting for smoking, ethnicity, caffeine intake, and other
covariates. There was no association between a family history of
colorectal, lung, prostate, or breast cancer and PD risk. The findings
supported the notion that melanoma and Parkinson disease share common
genetic components.

INHERITANCE

There has been much controversy regarding the genetics of Parkinson
disease, as no specific pattern of inheritance is readily apparent, and
reports of Parkinson disease and parkinsonism may not necessarily refer
to the same disease entity (Nussbaum and Polymeropoulos, 1997). However,
a familial component to Parkinson disease and parkinsonism has long been
recognized.

Gowers (1900) is believed to have been the first to observe that
patients with PD often had an affected relative, and he suggested that
hereditary factors may be important. Bell and Clark (1926) reviewed
published pedigrees of 'paralysis agitans' and reported an additional
one. Allan (1937) described impressive pedigrees from North Carolina.

- Twin Studies

Kissel and Andre (1976) described a pair of female MZ twins, both of
whom had a combination of parkinsonism and anosmia. Olfactory impairment
is frequent in PD (Ward et al., 1983). Both twins reported onset of
symptoms at age 36 years, which is unusually early, particularly for
women (Kessler, 1978). Kissel and Andre (1976) noted that 2 families
with the same association had previously been reported and they
suggested a causative role for a genetically determined anomaly of
dopamine metabolism.

Duvoisin et al. (1981) found zero concordance for Parkinson disease in
the first 12 monozygotic twin pairs examined in an on-going twin study.
There was evidence of premorbid personality differences between probands
and cotwins dating back to late adolescence or early adult years. Among
43 monozygotic and 19 dizygotic twin pairs, Ward et al. (1983) found
that only 1 monozygotic twin pair was definitely concordant for PD. Ward
et al. (1983) noted that concordance for PD is no more frequent in twins
than would be expected from the incidence of the disease, and concluded
that major factors in the etiology of PD must be nongenetic.

- Mendelian Inheritance

Spellman (1962) described a family in which multiple members in 4
generations had parkinsonism beginning in their thirties and progressing
rapidly to death in 2 to 12 years. Tune et al. (1982) described
Parkinson disease in 4 persons in 3 generations. Several of these also
had manic-depressive illness.

Barbeau and Pourcher (1982, 1983) suggested that mendelian inheritance
obtains in some cases, particularly in those whose illness started
before the age of 40. In this early-onset group, there was a 46%
incidence of familial cases. They divided Parkinson disease into 4
etiologic categories: postencephalitic, idiopathic, genetic, and
symptomatic. They proposed the existence of 2 genetic subtypes: an
akineto-rigid subtype transmitted as an autosomal recessive and a
subtype with prominent tremor, dominant inheritance, and a high
prevalence of family members with essential tremor.

Lazzarini et al. (1994) found that the cumulative risk of PD among sibs
of probands with affected parents was increased significantly over that
for sibs of probands without affected parents, suggesting significant
familial aggregation in a subset of randomly ascertained families.
Furthermore, in 80 multicase families, age-adjusted ratios approaching
0.5 and similar proportions of affected parents and sibs, as well as the
distribution of ancestral secondary cases, were compatible with an
autosomal dominant mode of inheritance with reduced penetrance in a
subset of PD. Payami et al. (1995) studied age of onset of 137 patients
with idiopathic Parkinson disease. The 21 probands with an affected
parent, aunt, or uncle were younger at onset of PD (47.7 +/- 8.8 years)
than were the 11 probands with an affected sib only (60.3 +/- 12.9
years) and the 105 probands with no affected relatives (59.2 +/- 11.4
years). Age of onset of affected family members differed significantly
between generations (p = 0.0001) and was earlier, by an average of 17
years, in the proband generation than in the parental generation. The
data were consistent with genetic anticipation and suggested the
involvement of an unstable trinucleotide repeat. Markopoulou et al.
(1995) studied a Greek-American kindred with 98 individuals in 6
generations. Sixteen individuals in 3 generations developed
parkinsonism, which appeared to be transmitted in an autosomal dominant
manner with evidence of anticipation. No pathologic data were presented.

Plante-Bordeneuve et al. (1995) studied 14 families in which the proband
and at least one relative were affected by clinically typical Parkinson
disease, based on Parkinson Disease Society brain bank diagnostic
criteria (Hughes et al., 1992). No clinical differences were found
between 31 individuals with familial Parkinson disease and 31
age-matched sporadic Parkinson disease controls. In the 14 families,
genetic transmission was compatible with autosomal dominant transmission
with several cases of male-to-male transmission. Although the total
segregation ratio was 0.25, this was age-dependent, with a penetrance of
zero below age 30 and a penetrance of 0.43 over the age of 70. Age at
onset was identical within a generation but it was 26 +/- 4.6 years
earlier in children than parents of the 8 multigenerational kindreds
studied, suggesting an anticipation phenomenon.

Bonifati et al. (1995) used epidemiologic methods to determine the
frequency of clinical features of familial Parkinson disease. By
studying 100 consecutive Parkinson disease cases presenting to their
clinic, family history for Parkinson disease was positive in 24% of
Parkinson disease cases and in only 6% of spouse controls. In a larger
study of 22 nonconsecutive Parkinson disease families with at least 2
living and personally examined cases, the crude segregation ratios were
similar for parents and sibs, with lifetime cumulative risks approaching
0.4. This data supported autosomal dominant inheritance with a strong
age factor in penetrance.

Nussbaum and Polymeropoulos (1997) reviewed the genetics of Parkinson
disease. They stated that for the previous 40 years, research into
Parkinson disease had predominantly been the province of epidemiologists
interested in pursuing the connection between the disorder and
environmental factors such as viral infection or neurotoxins. Hereditary
influences were discounted because of a high discordance rate among
monozygotic twins found in studies that were later shown to be
inadequate and inconclusive. On the other hand, a positive family
history was recognized as a major risk factor for the disease and it
became increasingly apparent from neuropathologic studies that the
common, idiopathic form of Parkinson disease had a specific pathologic
correlate in the form of Lewy bodies, an eosinophilic cytoplasmic
inclusion body, distributed diffusely throughout the substantia nigra,
hypothalamus, hippocampus, autonomic ganglia, and olfactory tracts. They
referred to the 'particularly prescient paper' of Sommer and Rocca
(1996), in which the authors suggested that autosomal dominant PD may be
caused by a missense mutation in a cellular protein that changes its
physical-chemical properties, leading to accumulation of the abnormal
protein and neuronal death. This hypothesis has received substantial
support.

Maher et al. (2002) collected information involving the nuclear families
of 948 consecutively ascertained Parkinson disease index cases from 3
U.S. medical centers. They performed segregation analysis to assess
evidence for the presence of a mendelian pattern of familial
transmission. The proportion of male (60.4%) and female (39.6%) cases,
the mean age of onset (57.7 years), and the proportion of affected
fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were
similar across the 3 institutions. They concluded that the analyses
supported the presence of a rare major mendelian gene for PD in both the
age-of-onset and susceptibility model. The age-of-onset model provided
evidence for a gene that influences age-dependent penetrance of PD,
influencing age of onset rather than susceptibility. Maher et al. (2002)
also found evidence for a mendelian gene influencing susceptibility to
the disease. It was not evident whether these 2 analyses were modeling
the same gene or different genes with different effects on PD. Genes
influencing penetrance may interact with environmental factors or other
genes to increase the risk of PD. Such gene-environment interactions,
involving reduced penetrance in PD, may explain the low concordance
rates among monozygotic twins for this disorder.

In a comparison of 221 PD patients with age at onset of 50 years or
younger, 266 PD patients with age at onset of 50 years or greater, and
409 unaffected controls, Marder et al. (2003) found a similar relative
risk (RR) of PD among first-degree relatives of both the early- and
late-onset groups (RR = 2.9 and 2.7, respectively) compared to those of
controls. There was also an increased risk of PD in sibs of affected
patients (RR = 7.9 for early-onset and 3.6 for late-onset) compared to
those of controls. Parents of the early-onset group were not at a
significantly increased risk compared to those of controls (RR = 1.7),
and parents of the late-onset group were at a higher increased risk
compared to those of controls (RR = 2.5). Marder et al. (2003) concluded
that the pattern was consistent with an autosomal recessive contribution
to the inheritance of early- but not late-onset PD, but also noted that
genetic factors are important in both groups.

- 'Familial Component'

Zareparsi et al. (1998) performed complex segregation analyses using
kindreds of 136 Parkinson disease patients randomly ascertained from a
clinic population. They rejected the hypotheses of a nontransmissible
environmental factor, a major gene or type (sporadic), and all mendelian
inheritance (dominant, recessive, additive, decreasing). They concluded
that familial clustering of PD in this dataset was best explained by a
'rare familial factor' which is transmitted in a nonmendelian fashion
and influences the age at onset of PD.

Montgomery et al. (1999) used a previously reported PD test battery to
check for mild signs of motor slowing, impaired sense of smell, and
depressed mood in first-degree relatives of patients with Parkinson
disease, most of whom were considered sporadic cases. Abnormalities on
the test battery were found in 22.5% of first-degree relatives, all of
whom were judged normal on standard neurologic examination, but in only
9% of age-matched controls. The authors interpreted this familial
clustering of minimal parkinsonian tendencies as an indication of
genetic predisposition to Parkinson disease even in sporadic cases.

Sveinbjornsdottir et al. (2000) reviewed the medical records and
confirmed the diagnosis of Parkinson disease in 772 living and deceased
patients in whom the diagnosis had been made in Iceland during the
previous 50 years. With the use of an extensive computerized database
containing genealogic information on 610,920 people in Iceland over the
past 11 centuries, they conducted several analyses to determine whether
the patients were more related to each other than random members of the
population. They found that there was a genetic component to Parkinson
disease, including a subgroup of 560 patients with late-onset disease
(onset after 50 years of age): patients with Parkinson disease were
significantly more related to each other than were subjects in matched
groups of controls, and this relatedness extended beyond the nuclear
family. There was no highly penetrant mendelian pattern of inheritance,
and both early and late-onset forms often skipped generations. The risk
ratio for Parkinson disease was 6.7 for sibs, 3.2 for offspring, and 2.7
for nephews and nieces of patients with late-onset Parkinson disease.

Racette et al. (2002) described a very large Amish pedigree with classic
idiopathic Parkinson disease in multiple members. They examined 113
members and classified 67 as having no evidence of PD, 17 as clinically
definite PD, 6 as clinically probable PD, and 23 as clinically possible
PD. The mean age at onset of the clinically definite subjects was 56.7
years. The mean kinship coefficient in the subjects with PD and those
with PD by history was higher (p = 0.007) than in a group of age-matched
normal Amish control subjects, providing evidence that PD is inherited
in this family. Sequence analysis did not reveal any mutations in known
PD genes. No single haplotype cosegregated with the disease in any of
the chromosomal regions previously found to be linked to PD.

- Environmental Factors

Some findings suggest that environmental factors may be more important
than genetic factors in familial aggregation of Parkinson disease. Calne
et al. (1987) reported 6 families in which onset of symptoms tended to
occur at approximately the same time regardless of the age of the
patient. In a hospital-based survey, Teravainen et al. (1986) concluded
that there is a trend toward lower age of onset of Parkinson disease.

Calne and Langston (1983) advanced the view that in most cases the cause
is an environmental factor, possibly toxic, superimposed on a background
of slow, sustained neuronal loss due to advancing age. Finding
parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropteridine
(meperidine; MPTP) drug users (Langston et al., 1983) revived interest
in reexamining environmental factors. Barbeau et al. (1985) also
postulated that Parkinson disease is the result of environmental factors
acting on genetically susceptible persons against a background of
'normal' aging.

Nathans (2005) noted the remarkable coincidence that the abbreviation
MPTP, for the drug that causes Parkinson disease by selectively damaging
dopaminergic neurons, is coincidentally the code for the first 4 amino
acids of human, mouse, and rat tyrosine hydroxylase, the enzyme which
marks all dopaminergic neurons.

In a case-control study of 418 Chinese PD patients and 468 controls, Tan
et al. (2007) found a significant association between caffeine intake
and decreased risk of PD (p = 2.01 x 10(-5)). The odds ratio was 0.48
for moderate and high caffeine intake and 0.71 for low intake. No
difference was observed with genotyping for a common SNP in the CYP1A2
gene (124060), which influences the level of caffeine metabolism. The
findings suggested that caffeine and its main metabolite paraxanthine
are both neuroprotective.

- Multifactorial Inheritance

Analysis of the experience at the Mayo Clinic led Kondo et al. (1973) to
conclude that irregular dominant transmission is untenable and that
multifactorial inheritance with heritability of about 80% is more
likely. Young et al. (1977) favored multifactorial inheritance but could
not exclude autosomal dominance with reduced penetrance, especially for
some families. Affected relatives were bilaterally distributed more
often than would be expected for autosomal dominance.

Vaughan et al. (2001) reviewed the genetics of parkinsonism. They
suggested that nigral degeneration with Lewy body formation and the
resulting clinical picture of Parkinson disease may represent a final
common pathway of a multifactorial disease process in which both
environmental and genetic factors have a role.

Also see review of Parkinson disease by Nussbaum and Ellis (2003).

- Mitochondrial Inheritance

Another theory of parkinsonism suggests that genetic predisposition may
be transmitted through mitochondrial inheritance (Di Monte, 1991); see
556500. Schapira (1995) reviewed nuclear and mitochondrial genetics in
Parkinson disease. He stated that Gowers (1900) had noted the occurrence
of PD in relatives and suggested that hereditary factors are important.

From a study of Parkinson disease in twins, Tanner et al. (1999)
concluded that 'no genetic component was evident when the disease begins
after age 50 years.' Parker et al. (1999) and Simon (1999) pointed out
that whereas this may be true as far as mendelian (nuclear) genetic
mechanisms are concerned, this may not be true for mitochondrial factors
in Parkinson disease. Since MZ and DZ twins each receive all of their
mitochondrial DNA from their mother, differences in concordance rates
between MZ and DZ twins cannot be used to address the potential
influence of mitochondrial genetic factors.

To test the hypothesis that mitochondrial variation contributes to
Parkinson disease expression, van der Walt et al. (2003) genotyped 10
single-nucleotide polymorphisms that define the European mitochondrial
DNA haplogroups in 609 white patients with Parkinson disease and 340
unaffected white control subjects. Overall, individuals classified as
haplogroup J (odds ratio = 0.55; 95% CI 0.34-0.91; p = 0.02) or K (odds
ratio = 0.52; 95% CI 0.30-0.90; p = 0.02) demonstrated a significant
decrease in risk of Parkinson disease versus individuals carrying the
most common haplogroup H. Furthermore, a specific SNP that defines these
2 haplogroups, 10398G (516002.0002), is strongly associated with this
protective effect (odds ratio = 0.53; 95% CI 0.39-0.73; p = 0.0001). The
10398G SNP causes a nonconservative amino acid change from threonine to
alanine within the ND3 (516002) of complex I. After stratification by
sex, this decrease in risk appeared stronger in women than in men. In
addition, the 9055A SNP of ATP6 (516060) demonstrated a protective
effect for women. Van der Walt et al. (2003) concluded that ND3 is an
important factor in Parkinson disease susceptibility among white
individuals and could help explain the role of complex I in Parkinson
disease expression.

CLINICAL MANAGEMENT

Gill et al. (2003) delivered glial cell line-derived neurotrophic factor
(GDNF; 600837) directly into the putamen of 5 Parkinson patients in a
phase 1 safety trial. One catheter needed to be repositioned and there
were changes in the MRIs that disappeared after lowering the
concentration of GDNF. After 1 year, there were no serious clinical side
effects, a 39% improvement in the off-medication motor subscore of the
Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in
the activities of daily living subscore. Medication-induced dyskinesias
were reduced by 64% and were not observed off medication during chronic
GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine
uptake showed a significant 28% increase in putamen dopamine storage
after 18 months, suggesting a direct effect of GDNF on dopamine
function.

Voon et al. (2007) evaluated 21 patients with Parkinson disease who
developed pathologic gambling (606349) after receiving pharmacologic
treatment with dopaminergic agonists. Compared to 42 PD patients without
compulsive behaviors, those who developed pathologic gambling had a
younger age at PD onset, higher novelty seeking (601696), tended to have
medication-induced hypomania or mania, impaired planning, and a personal
or family history of alcohol use disorders (103780).

L-dopa is predominantly metabolized to the inactive 3-O-methyldopa by
COMT (116790). Entacapone is a COMT inhibitor that acts to prolong the
half-life of L-dopa and yields prolonged therapeutic benefits. A
val158-to-met (V158M) polymorphism in the COMT gene (dbSNP rs4680;
116790.0001) confers increased (val) or decreased (met) COMT activity.
In a randomized control trial of 33 PD patients, Corvol et al. (2011)
found that those homozygous for the high-activity val158 allele had
significantly increased COMT inhibition by entacapone and significantly
better bioavailability of and clinical response to L-dopa compared to
patients homozygous for the low-activity met158 allele. The findings
indicated that homozygosity for the val158 allele in PD patients
enhances the effect of entacapone on the pharmacodynamics and
pharmacokinetics of levodopa. The response to entacapone in heterozygous
patients was not studied.

Using unbiased phenotypic screens as an alternative to target-based
approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole
(NAB) that strongly and selectively protected diverse cell types from
alpha-synuclein (163890) toxicity. Three chemical genetic screens in
wildtype yeast cells established that NAB promoted endosomal transport
events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These
same steps were perturbed by alpha-synuclein itself. Tardiff et al.
(2013) concluded that NAB identifies a druggable node in the biology of
alpha-synuclein that can correct multiple aspects of its underlying
pathology, including dysfunctional endosomal and endoplasmic
reticulum-to-Golgi-vesicle trafficking.

Chung et al. (2013) exploited mutation correction of iPS cells and
conserved proteotoxic mechanisms from yeast to humans to discover and
reverse phenotypic responses to alpha-synuclein, a key protein involved
in Parkinson disease. Chung et al. (2013) generated cortical neurons
from iPS cells of patients harboring alpha-synuclein mutations (A53T;
163890.0001), who are at high risk of developing PD dementia. Genetic
modifiers from unbiased screens in a yeast model of alpha-synuclein
toxicity led to identification of early pathogenic phenotypes in patient
neurons, including nitrosative stress, accumulation of endoplasmic
reticulum-associated degradation substrates, and ER stress. A small
molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin
ligase that it affects, reversed pathologic phenotypes in these neurons.

MAPPING

- Evidence for Genetic Heterogeneity

Polymeropoulos et al. (1996) demonstrated genetic linkage between an
autosomal dominant form of PD and genetic markers on 4q21-q23. The locus
was designated PARK1 (168601). In 94 Caucasian families, Scott et al.
(1997) could not demonstrate linkage to 4q21-q23. They also found no
linkage even when the 22 families from their study with at least 1 case
of early-onset PD were examined separately. Gasser et al. (1997)
excluded linkage in 13 multigenerational families with Parkinson
disease, with the exception of 1 family for which they achieved a
maximum multipoint lod score of 1.5 for genetic markers in the 4q21-q23
region.

Scott et al. (2001) described a genetic linkage study conducted in
1995-2000 in which a complete genomic screen was performed in 174
families with multiple individuals diagnosed as having idiopathic PD,
identified through probands in 13 clinic populations in the continental
United States and Australia. Significant evidence for linkage was found
in 5 distinct chromosomal regions: chromosome 6 in the parkin gene
(PARK2; 602544) in families with at least 1 individual with PD onset at
younger than 40 years (lod = 5.47); chromosomes 17q (lod = 2.62), 8p
(lod = 2.22), and 5q (lod = 1.50) overall and in families with
late-onset PD; and 9q (lod = 2.59) in families with both
levodopa-responsive and levodopa-nonresponsive patients. The data
suggested that the parkin gene is important in early-onset PD and that
multiple genetic factors may be important in the development of
idiopathic, late-onset PD.

Pankratz et al. (2002) studied 160 multiplex families with PD in which
there was no evidence of mutations in the parkin gene, and used
multipoint nonparametric linkage analysis to identify PD susceptibility
genes. For those individuals with a more stringent diagnosis of verified
PD, the highest lod scores were observed on the X chromosome and on
chromosome 2 (lod scores equal to 2.1 and 1.9, respectively). Analyses
performed with all available sib pairs, i.e., all examined individuals
treated as affected regardless of their final diagnostic classification,
yielded even greater evidence of linkage to the X chromosome and to
chromosome 2 (lod scores equal to 2.7 and 2.5, respectively). Evidence
of linkage was also found to chromosomes 4, 5, and 13 (lod scores
greater than 1.5). Pankratz et al. (2002) considered their findings
consistent with those of other linkage studies that had reported linkage
to chromosomes X and 5.

Pankratz et al. (2003) studied 754 affected individuals, comprising 425
sib pairs, to identify PD susceptibility genes. Genomewide,
nonparametric linkage analyses revealed potential loci on chromosomes 2,
X, 10, and 14. The authors hypothesized that gene-by-gene interactions
are important in PD susceptibility.

- Associations Pending Confirmation

Maraganore et al. (2005) performed a 2-tiered, genomewide association
study of PD including 443 sib pairs discordant for PD and 332
case-unrelated control pairs. A SNP (dbSNP rs7702187) within the
semaphorin-5A gene (SEMA5A; 609297) on chromosome 5p had the lowest
combined p value (p = 7.62 x 10(-6)). The protein encoded by this gene
plays an important role in neurogenesis and in neuronal apoptosis, which
was consistent with hypotheses regarding PD pathogenesis.

Gao et al. (2009) conducted a genomewide linkage screen of 5,824 SNPs in
278 families of European non-Hispanic descent to localize regions that
harbor susceptibility loci for Parkinson disease. These 278 families
included 158 families included in a previous screen (Scott et al., 2001)
and 120 families not previously screened. In the overall screen of all
278 families, the highest multipoint MLOD scores were obtained under a
dominant model of inheritance in an 11-cM interval on chromosome 3q25
(MLOD = 2.0) and a 9-cM interval on chromosome 18q11 (MLOD = 1.8). Since
the combined screen did not detect linkage overall in regions previously
implicated, Gao et al. (2009) suspected that clinical and locus
heterogeneity might exist. They stratified the dataset into previously
screened and unscreened families. In the 120 families not previously
screened, Gao et al. (2009) achieved significant evidence for linkage on
chromosome 18q11 (maximum lod score = 4.1) and suggestive evidence on
chromosome 3q25 (maximum lod score = 2.5). There was little evidence for
linkage to these regions overall in the original 158 families.
Simulation studies suggested that these findings were likely due to
locus heterogeneity rather than random statistical error. See also
PARK18 (614251), which is caused by mutation in the EIF4G1 gene (600495)
on 3q27.

To identify susceptibility variants for Parkinson disease, Satake et al.
(2009) performed a genomewide association study and 2 replication
studies in a total of 2,011 cases and 18,381 controls from Japan. They
identified a novel susceptibility locus on chromosome 4p15. Four SNPs
(dbSNP rs11931532, dbSNP rs12645693, dbSNP rs4698412, and dbSNP
rs4538475) reached p less than 5 x 10(-7) in the combined analysis. The
4 SNPs were located 4.1 kb downstream of intron 8 of the BST1 gene
(600387). Satake et al. (2009) also identified a locus on chromosome
1q32 (PARK16; 613164), replicated by Simon-Sanchez et al. (2009), and
replicated associations on 4q22 (see PARK1, 168601) and 12q12 (see
PARK8, 607060). Tan et al. (2010) confirmed associations at the PARK16,
PARK1, and PARK8 loci in 433 PD patients and 916 controls, all of
Chinese ethnicity. However, they did not identify a significant
association at the BST1 locus.

By a genomewide association study of 2,000 individuals with late-onset
PD and 1,986 unaffected controls, all of European ancestry from the
NeuroGenetics Research Consortium (NGRC), Hamza et al. (2010) found an
association between PD and dbSNP rs11248051 in the GAK gene (602052) on
chromosome 4p (p = 3.1 x 10(-4); odds ratio (OR) of 1.32). When combined
with data from a previous study (Pankratz et al., 2009), metaanalysis of
the combined dataset of 2,843 patients yielded a significant association
(p = 3.2 x 10(-9); OR, 1.46). Hamza et al. (2010) designated this
possible locus PARK17, but that symbol has been used for a confirmed PD
locus on chromosome 16q13 (see 614203). They also found a significant
association between PD and dbSNP rs3129882 in intron 1 of the HLA-DRA
(142860) gene on chromosome 6p21.3 (p = 2.9 x 10(-8)). The authors
designated this possible locus PARK18, but that symbol has been used for
a confirmed PD locus on chromosome 3q27 (see 614251). The association
was significant even after adjusting for age, sex, and genetic
substructure among Americans of European descent (as defined by Jewish
ancestry and country of origin). The findings were replicated in 2
datasets comprising 1,447 patients, and metaanalysis of the 3
populations showed a combined p value of 1.9 x 10(-10) and odds ratio of
1.26. The HLA association was uniform across all genetic and
environmental risk strata, and was strong in both sporadic (p = 5.5 x
10(-10)) and late-onset (p = 2.4 x (10-8)) disease. A data repository of
expression QTL indicated that dbSNP rs3129882 is a cis-acting regulatory
variant that correlated significantly with expression levels of HLA-DRA,
HLA-DQA2 (613503), and HLA-DRB5 (604776). Hamza et al. (2010) suggested
that their findings supported the involvement of the immune system in
the pathogenesis of Parkinson disease. However, Mata et al. (2011)
failed to replicate the associations between Parkinson disease and the
loci at chromosome 4p and 6p21 in a study of 1,445 PD patients and 1,161
controls from northern Spain. The SNPs studied included dbSNP rs11248051
in the GAK gene and dbSNP rs3129882 in the HLA-DRA gene. Mata et al.
(2011) concluded that the loci designated PARK17 and PARK18 by Hamza et
al. (2010) required further validation.

MOLECULAR GENETICS

Investigating the postulate that PD may have an environmental cause,
Barbeau et al. (1985) noted that many potential neurotoxic xenobiotics
are detoxified by hepatic cytochrome P450. They studied one such system
in 40 patients with Parkinson disease and 40 controls, and found that
significantly more patients than controls had partially or totally
defective 4-hydroxylation of debrisoquine (608902). Poor metabolizers
had earlier onset of disease. Bordet et al. (1994) investigated a
genetic polymorphism of the cytochrome P450 CYP2D6 gene (124030) in 105
patients with idiopathic Parkinson disease and 15 patients with diffuse
Lewy body disease. They found no relationship between the CYP2D6 gene
associated with poor metabolism of debrisoquine with either idiopathic
Parkinson disease or diffuse Lewy body disease. Sandy et al. (1996)
found no significant differences in CYP2D6 allelic frequencies between
early-onset Parkinson disease cases (51 years of age or less) and
controls.

Kurth et al. (1993) found a single-strand conformation polymorphism in
intron 13 of the monoamine oxidase B gene (309860) and found a
significantly higher frequency of 1 allele in their parkinsonian
population compared with the control group. Ho et al. (1995), however,
were unable to substantiate this claim.

Parboosingh et al. (1995) failed to find pathogenic mutations in either
copper/zinc (147450) or manganese (147460) superoxide dismutase or in
catalase (115500) in a single-strand conformation analysis of 107
unrelated patients with Parkinson disease, which included both familial
and sporadic cases.

Polymeropoulos (1997) noted that Polymeropoulos et al. (1997) had
reported a total of 4 families in which mutation in the alpha-synuclein
gene (SNCA; 163890) could be shown to be responsible for early-onset
Parkinson disease. However, mutation was not detected in 50 individuals
with sporadic Parkinson disease or in 2 other families with late onset
of the illness.

Wu et al. (2001) analyzed 224 Taiwanese patients with PD for MAOB intron
13 G (309860) and COMT L (V158M; 116790.0001) polymorphisms and found
that the MAOB G genotype (G in men, G/G in women) was associated with a
2.07-fold increased relative risk for PD, an association which was
stronger for men than for women. Although COMT polymorphism alone was
not associated with an increased risk for PD, when it was considered in
conjunction with the MAOB G genotype, there was a 2.4-fold increased
relative risk for PD. In men, the combined alleles, MAOB G and COMT L,
increased the relative risk for PD to 7.24. Wu et al. (2001) suggested
that, in Taiwanese, the development of PD may be related to the
interaction of 2 or more genes involved in dopamine metabolism.

The demonstration of linkage of idiopathic Parkinson disease to 17q21
(Scott et al., 2001) made the tau gene (MAPT; 157140) a good candidate
as a susceptibility gene for idiopathic PD. Martin et al. (2001) tested
5 single-nucleotide polymorphisms (SNPs) within the MAPT gene for
association with PD in a sample of 1,056 individuals from 235 families
selected from 13 clinical centers in the United States and Australia and
from a family ascertainment core center. They used family-based tests of
association. The sample consisted of 426 affected and 579 unaffected
family members; 51 individuals had unclear PD status. Both individual
SNPs and SNP haplotypes in the MAPT gene were analyzed. Significant
evidence of association was found for 3 of the 5 SNPs tested. Strong
evidence of association was found with haplotype analysis, with a
positive association with 1 haplotype (p = 0.009) and a negative
association with another haplotype (p = 0.007). Substantial linkage
disequilibrium (p less than 0.001) was detected between 4 of the 5 SNPs.
The study was interpreted as implicating MAPT as a susceptibility gene
for idiopathic Parkinson disease.

Kwok et al. (2005) identified 2 functional SNPs in the GSK3B (605004)
gene that influenced GSK3B transcriptional activity and correlated with
enhanced phosphorylation of MAPT in vitro, respectively. Conditional
logistic regression analysis of the genotypes of 302 Caucasian PD
patients and 184 Chinese PD patients found an association between the
GSK3B polymorphisms, MAPT haplotype, and risk of PD. Kwok et al. (2005)
concluded that GSK3B polymorphisms interact with MAPT haplotypes to
modify disease risk in PD.

Among 52 Finnish patients with PD, Mattila et al. (2002) found an
increased frequency of the interleukin 1-beta gene (IL1B; 147720) -511
polymorphism compared to controls (allele frequency of 0.96 in PD and
0.73 in controls; p = 0.001). The calculated relative risk of PD for
patients carrying at least one IL1B allele was 8.8.

West et al. (2002) reported that a single-nucleotide polymorphism within
the parkin core promoter, -258T/G, is located in a region of DNA that
binds nuclear protein from human substantia nigra in vitro, and
functionally affects gene transcription. In a population-based series of
296 PD cases and 184 controls, the -258G allele was associated with
idiopathic PD (odds ratio 1.52, P less than 0.05).

Excess of nitric oxide (NO) has been shown to exert neurotoxic effects
in the brain. Moreover, inhibition of 2 enzyme isoforms of nitric oxide
synthase (NOS; see 163731), neuronal NOS (nNOS) and inducible NOS
(iNOS), results in neuroprotective effects in the MPTP model of PD.
Levecque et al. (2003) performed a community-based case-control study of
209 PD patients enrolled in a French health insurance organization for
agricultural workers and 488 European controls. Associations were
observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS
22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01), and a T-to-C
polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of
the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was
observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS
18. Moreover, a significant interaction of the nNOS polymorphisms with
current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS
29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a
modifier gene in PD.

Chan et al. (2003) found that the slow acetylator (243400) genotype for
N-acetyltransferase-2 (NAT2; 612182) was associated with PD in Hong Kong
Chinese. The frequency of slow acetylator genotype was significantly
higher in 99 patients with PD than in 126 control subjects (68.7% vs
28.6%) with an odds ratio of 5.53 after adjusting for age, sex, and
smoking history. In a subgroup analysis, smoking had no modifying effect
on the association between genotype and PD.

In 2 apparently sporadic patients with Parkinson disease, Marx et al.
(2003) found an arg621-to-cys (R621C) mutation in synphilin-1
(603779.0001).

Li et al. (2002) reported genetic linkage of a locus controlling age at
onset in Alzheimer disease (AD; 104300) and PD to a 15-cM region on
chromosome 10q. Li et al. (2003) combined gene expression studies on
hippocampus obtained from AD patients and controls with their previously
reported linkage data to identify 4 candidate genes. Allelic association
studies for age-at-onset effects in 1,773 AD patients and 1,041
relatives and 635 PD patients and 727 relatives further limited
association to GSTO1 (605482) (p = 0.007) and a second transcribed
member of the GST omega class, GSTO2 (612314) (p = 0.005), located next
to GSTO1. The authors suggested that GSTO1 may be involved in the
posttranslational modification of IL1B.

Theuns et al. (2006) pointed out that it is widely accepted that genetic
causes of susceptibility to complex diseases reflect a different
spectrum of sequence variants than mutations that dominate monogenic
disorders. This spectrum includes mutations that alter gene expression;
in particular, promoter mutations have been shown to result in inherited
diseases, including neurodegenerative brain diseases. They pointed to
the fact that in Parkinson disease, 2 variants in the 5-prime regulatory
region of NR4A2 (601828.0001 and 601828.0002) were found to be
associated with familial PD and markedly reduced NR4A2 mRNA levels.
Also, multiple association studies showed that variations in the 5-prime
regulatory regions of SNCA (163890) and PARK2 (602544) increase PD
susceptibility, with some variations increasing disease risk by
modulating gene transcription. In Alzheimer disease (104300), promoter
mutations in PSEN1 (104311) can explain the increased risk for
early-onset AD by decreasing expression levels of PSEN1 in neurons.

Considering 4 putative PD risk regions, SNCA, MAPT, GAK, and HLA-DRA in
2,000 late-onset PD patients and 1,986 unaffected controls from the NGRC
population, Hamza et al. (2010) found that the risk of Parkinson disease
was doubled for individuals who had 4 risk alleles (OR of 2.49, p = 6.5
x 10(-8)), and was increased 5-fold for individuals who had 6 or more
risk alleles (OR of 4.95, p = 5.5 x 10(-13)). These findings supported
the notion that Parkinson disease risk is due to cumulative effects of
risk factors that each have a modest individual effect.

- Association with the Glucocerebrosidase (GBA) Gene

An association has been reported between parkinsonism and type I Gaucher
disease (230800) (Neudorfer et al., 1996; Tayebi et al., 2001; Bembi et
al., 2003), the most prevalent, recessively inherited disorder of
glycolipid storage. Simultaneous occurrence of Parkinson disease and
Gaucher disease is marked by atypical parkinsonism generally presenting
by the fourth through sixth decades of life. The combination progresses
inexorably and is refractory to conventional anti-Parkinson therapy
(Varkonyi et al., 2003).

Aharon-Peretz et al. (2004) studied the association of Parkinson disease
with Gaucher disease, which is caused by mutation in the GBA gene
(606463), which encodes the lysosomal enzyme glucocerebrosidase. They
screened 99 Ashkenazi patients with idiopathic Parkinson disease, 74
Ashkenazi patients with Alzheimer disease, and 1,543 healthy Ashkenazi
Jews for the 6 GBA mutations that are most common among Ashkenazi Jews.
One or 2 mutant GBA alleles were found in 31 patients with Parkinson
disease (31.3%): 28 were heterozygous and 3 were homozygous for one of
these mutations. Among the 74 patients with Alzheimer disease, 3 (4.1%)
were carriers of Gaucher disease. Among the 1,543 controls, 95 (6.2%)
were carriers of Gaucher disease. Patients with Parkinson disease had
significantly greater odds of being carriers of Gaucher disease than did
patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0).
Among the patients with Parkinson disease, those who were carriers of
Gaucher disease were younger than those who were not carriers (mean age
at onset, 60.0 years vs 64.2 years, respectively). Aharon-Peretz et al.
(2004) suggested that some GBA mutations are susceptibility factors for
Parkinson disease.

Toft et al. (2006) did not find an association between PD and 2 common
GBA mutations (L444P; 606463.0001 and N370S; 606463.0003) among 311
Norwegian patients with Parkinson disease. Mutant GBA alleles were
identified in 7 (2.3%) patients and 8 (1.7%) controls.

Tan et al. (2007) identified a heterozygous GBA L444P mutation in 8
(2.4%) of 331 Chinese patients with typical Parkinson disease and none
of 347 controls. The age at onset was lower and the percentage of women
higher in patients with the L444P mutation compared to those without the
mutation. Tan et al. (2007) noted that the findings were significant
because Gaucher disease is extremely rare among the Chinese.

Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish
patients with PD carried a GBA mutation, compared to 4.2% of elderly and
6.35% of young controls. The proportion of severe GBA mutation carriers
among patients was 29% compared to 7% among young controls. Severe and
mild GBA mutations increased the risk of developing PD by 13.6- and
2.2-fold, and were associated with decreased age at PD onset. Gan-Or et
al. (2008) concluded that genetic variance in the GBA gene is a risk
factor for PD.

Gutti et al. (2008) identified the GBA L444P mutation in 4 (2.2%) of 184
Taiwanese patients with PD. Six other GBA variants were identified in 1
patient each, yielding a total of 7 different mutations in 10 patients
(5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA
gene would reveal additional variants that may contribute to PD.

Mata et al. (2008) identified heterozygosity for either the GBA L444P or
N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 patients
with Lewy body dementia, and 2 (0.4%) of 554 control subjects
individuals, all of European origin. Mata et al. (2008) estimated that
the population-attributable risk for GBA mutations in Lewy body
disorders was only about 3% in patients of European ancestry.

In a 16-center worldwide study comprising 5,691 PD patients (including
780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis),
Sidransky et al. (2009) demonstrated a strong association between GBA
mutations and Parkinson disease. Direct sequencing for only the L444P or
N370S mutations identified either mutation in 15% of Ashkenazi patients
and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either
mutation was found in 3% of patients and less than 1% of controls.
However, full gene sequencing identified GBA mutations in 7% of
non-Ashkenazi patients. The odds ratio for any GBA mutation in patients
compared to controls was 5.43 across all centers. Compared to PD
patients without GBA mutations, patients with GBA mutations presented
earlier with the disease, were more likely to have affected relatives,
and were more more likely to have atypical manifestations, including
cognitive defects. Sidransky et al. (2009) concluded that while GBA
mutations are not likely a mendelian cause of PD, they do represent a
susceptibility factor for development of the disorder.

Neumann et al. (2009) identified 14 different heterozygous mutations in
the GBA gene, in 33 (4.18%) of 790 British patients with Parkinson
disease and in 3 (1.17%) of 257 controls. Three novel mutations (see,
e.g., D443N; 606463.0048) were identified, and most common mutations
were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3
patients; 606463.0008). Four (12%) patients had a family history of the
disorder, whereas 29 (88%) had sporadic disease. The mean age at onset
was 52.7 years, and 12 (39%) patients had onset before age 50. Fifteen
(about 50%) patients with GBA mutations developed cognitive decline,
including visual hallucinations. The male to female ratio of GBA
carriers within the PD group was 5:2, which was significantly higher
than that of the whole study group. Most patients responded initially to
L-dopa treatment. Neuropathologic examination of 17 GBA mutation
carriers showed typical PD changes, with widespread and abundant
alpha-synuclein pathology, and most also had neocortical Lewy body
pathology. The prevalence of GBA mutations in British patients with
sporadic PD was 3.7%, indicating that mutations in the GBA gene may be
the most common risk factor for development of PD in this population. In
an accompanying letter, Gan-Or et al. (2009) found that the data
presented by Neumann et al. (2009) indicated that patients with mild GBA
mutations had a later age at onset (62.9 years vs 49.8 years) and lower
frequency of cognitive symptoms (25% vs 55.6%) compared to patients with
severe GBA mutations.

Alcalay et al. (2010) identified mutations in the GBA gene in 64 (6.7%)
of 953 patients with early-onset PD before age 51, including 77 and 139
individuals of Hispanic and Jewish ancestry, respectively. There were 18
heterozygous L444P carriers, 38 heterozygous N370S carriers, and 2
homozygous N370S carriers. Six of the 64 patients had a GBA mutation and
another mutation in the LRRK2 or PRKN (PARK2; 602544) genes.

- Modifier Genes

Plaitakis et al. (2010) identified a 1492T-G polymorphism in the GLUD2
gene (S445A; 300144.0001) that was associated with earlier age of onset
in 2 cohorts of patients with Parkinson disease. Among 584 Greek
patients, 1492G hemizygous males developed PD 8 to 13 years earlier than
did patients with the T (p = 0.003), the G/T (p less than 0.001), or the
T/T (p = 0.01) genotype. Among 224 North American patients, 1492G
hemizygotes also developed PD earlier than those with other genotypes,
but the mean age differences reached statistical significance only when
G hemizygotes were compared to G/T heterozygotes (mean age difference:
13.1 years, p less than 0.05). The substitution was demonstrated to
confer a gain of function, which Plaitakis et al. (2010) postulated may
increase glutamate oxidation and the production of reactive oxygen
species in the brain.

GENOTYPE/PHENOTYPE CORRELATIONS

Mutations in the LRRK2 gene (609007) and the GBA gene commonly
predispose to PD in individuals of Ashkenazi Jewish descent. Gan-Or et
al. (2010) screened a cohort of 600 Ashkenazi PD patients for the common
LRRK2 G2019S mutation (609007.0006) and for 8 GBA mutations. Among all
patients, 117 (19.5%) were heterozygous for GBA mutations, and 82
(13.7%) were heterozygous for the LRRK2 G2019S mutation, including 8
patients carrying both GBA and LRRK2 mutations. There were 6 (1.0%)
homozygotes or compound heterozygotes GBA mutations carriers, and 1
(0.2%) patient homozygote for G2019S. Carriers of LRRK2 G2019S or GBA
mutations had a significantly earlier average age at onset (57.5 and
57.7 years) than noncarriers (61.0 years); the 8 with mutations in both
genes had a similar average age at onset (57.4 years). A phenotypic
comparison of those with the G2019S mutation, GBA mutations, and
noncarriers of these mutations showed that more of those with the G2019S
mutation reported muscle stiffness/rigidity (p = 0.007) and balance
disturbances (p = 0.008), while more GBA mutation carriers reported
slowness/bradykinesia (p = 0.021). However, the most common presenting
symptom in both groups was tremor (about 50%). These results suggested
distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD
in some cases.

PATHOGENESIS

Nussbaum and Polymeropoulos (1997) stated that the motor symptoms in
Parkinson disease are generally thought to result from the deficiency or
dysfunction of dopamine or dopaminergic neurons in the substantia nigra,
regardless of etiology.

Auluck et al. (2002) found that Lewy bodies and Lewy neurites in
postmortem brain tissue from Parkinson disease patients immunostained
for the molecular chaperones HSP70 (see 140550) and HSP40 (see 604572),
suggesting that chaperones may play a role in Parkinson disease
progression, as was demonstrated in their studies in flies carrying
mutated alpha-synuclein (163890) in which coexpression of human HSP70
mitigated the loss of dopaminergic neurons.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin
(RELN; 600514) fragment in CSF from 19 patients with AD compared to 11
nondemented controls. Western blot and PCR analysis confirmed increased
levels of reelin protein and mRNA in tissue samples from the frontal
cortex of AD patients. Reelin was not increased in plasma samples,
suggesting distinct cellular origins. The reelin 180-kD fragment was
also increased in CSF samples of other neurodegenerative disorders,
including frontotemporal dementia, PSP, and PD.

Cooper et al. (2006) found that the earliest defect following
alpha-synuclein expression in yeast was a block in endoplasmic
reticulum-to-Golgi vesicular trafficking. In a genomewide screen, the
largest class of toxicity modifiers were proteins functioning at this
same step, including the Rab guanosine triphosphate Ypt1p, which
associated with cytoplasmic alpha-synuclein inclusions. Elevated
expression of Rab1 (179508), the mammalian Ypt1 homolog, protected
against alpha-synuclein-induced dopaminergic neuron loss in animal
models of PD. Thus, Cooper et al. (2006) concluded that
synucleinopathies may result from disruptions in basic cellular
functions that interface with the unique biology of particular neurons
to make them especially vulnerable.

Outeiro et al. (2007) identified a potent inhibitor of sirtuin-2
(604480) and found that inhibition of SIRT2 rescued alpha-synuclein
toxicity and modified inclusion morphology in a cellular model of
Parkinson disease. Genetic inhibition of SIRT2 via small interfering RNA
similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors
protected against dopaminergic cell death both in vitro and in a
Drosophila model of PD. Outeiro et al. (2007) concluded that their
results suggest a link between neurodegeneration and aging.

Muqit et al. (2006) provided a review of the role of mitochondrial
dysfunction, including oxidative damage and apoptosis, in the
pathogenesis of Parkinson disease.

Elstner et al. (2009) performed whole-genome expression profiling of
isolated substantia nigra neurons taken from 8 patients with PD and 9
controls. Four differentially expressed genes were identified in
candidate PD pathways: MTND2 (516001, p = 7.14 x 10(-7)); PDXK (179020,
p = 3.27 x 10(-6)); SRGAP3 (606525, p = 5.65 x 10(-6)); TRAPPC4 (610971,
p = 5.81 x 10(-6)). Population-based studies found an association
between dbSNP rs2010795 in the PDXK gene and increased risk of PD in
German (p = 0.00032), British (p = 0.028), and Italian (p = 0.0025)
cohorts (combined p = 1.2 x 10(-7); OR of 1.3) totaling 1,232 PD
patients and 2,802 controls. Elstner et al. (2009) suggested that
vitamin B6 status and metabolism may influence disease risk in PD.
However, neither Guella et al. (2010) nor Vilarino-Guell et al. (2010)
could replicate the association with dbSNP rs2010795 in their respective
studies of 920 Italian PD patients and 920 Italian controls and of 6
independent populations from Europe, North America, and Asia totaling
1,977 PD patients and 1,907 controls.

In brains from patients with Parkinson disease, Minones-Moyano et al.
(2011) found decreased expression of MIRN34B (611374) and MIRN34C
(611375) in areas with variable neuropathologic affectation at different
clinical stages of the disease, including the amygdala, frontal cortex,
substantia nigra, and cerebellum. Misregulation of MIRN34B/C was
detected in pre-motor stages of the disease as well, particularly in the
amygdala. Depletion of MIRN34B or MIRN34C in differentiated dopaminergic
neuronal cells resulted in a moderate reduction in cell viability that
was accompanied by altered mitochondrial function and dynamics,
oxidative stress, and reduction in total cellular ATP content.
Downregulation of these miRNAs was associated with a decrease in the
expression of DJ1 (602533) and PARK2 (602544), 2 genes associated with
PD, in cell studies and in patient brain tissue. The findings suggested
that early deregulation of MIRN34B and MIRN34C can trigger downstream
transcriptome alterations underlying mitochondrial dysfunction and
oxidative stress, which ultimately compromise cell viability in PD.

POPULATION GENETICS

Trenkwalder et al. (1995) used a door-to-door survey to investigate the
prevalence of parkinsonism in a rural Bavarian population of individuals
older than 65 years. In this population, the prevalence of Parkinson
disease was 0.71%; drug-induced parkinsonism, 0.41%; vascular
parkinsonism, 0.20%; multiple systems atrophy, 0.31%; Fahr disease,
0.10%; and normal pressure hydrocephalus, 0.41%. Fifty percent of these
cases were newly diagnosed.

In a community-based survey of Singaporeans (9,000 Chinese, 3,000
Malays, and 3,000 Indians) aged 50 years and older, Tan et al. (2004)
found that the prevalence rate of PD was approximately 0.30%, which is
comparable to that of Western countries.

In a study of over 14,000 twin pairs in the Swedish Twin Registry,
Wirdefeldt et al. (2004) found that only 2 twin pairs were concordant
for PD, suggesting that environmental factors were more important in the
development of the disease in this population.

HISTORY

Parkinson disease was first described by physician James Parkinson as a
'shaking palsy' in 1817. Stien (2005) proposed that William Shakespeare
(1564-1616) referred to the disease as a 'palsy' of old age in several
of his plays, indicating that the first European reference to the
disease occurred in the late 16th century.

Zhang et al. (2006) provided a detailed review of early Chinese
descriptions of Parkinson disease, including contemporary therapeutic
recommendations. The evidence from classic sources of traditional
Chinese medicine strongly suggested that PD was known to medical
scholars in China as early as 425 B.C.; the first clear description of a
clinical case occurred during the Jin dynasty in late 12th century A.D.

ANIMAL MODEL

Clarke et al. (2000) studied the kinetics of neuronal death in 12 models
of photoreceptor degeneration, hippocampal neurons undergoing
excitotoxic cell death, a mouse model of cerebellar degeneration, and in
Parkinson and Huntington (143100) diseases. In all models the kinetics
of neuronal death were exponential and better explained by mathematical
models in which the risk of cell death remains constant or decreases
exponentially with age. These kinetics argue against the cumulative
damage hypothesis; instead, the time of death in any neuron is random.
Clarke et al. (2000) argued that their findings are most simply
accommodated by a '1-hit' biochemical model in which mutation imposes a
mutant steady state on the neuron and a single event randomly initiates
cell death. This model appears to be common to many forms of
neurodegeneration and has implications for therapeutic strategies in
that the likelihood that a mutant neuron can be rescued by treatment is
not diminished by age, and therefore treatment at any stage of illness
is likely to confer benefit.

Progressive postnatal depletion of dopaminergic cells has been
demonstrated in weaver mice, a mouse model of Parkinson disease
associated with homozygosity for a mutation in the H54 region of Girk2,
a putative G protein inward rectifier protein potassium channel.
Bandmann et al. (1996) found no mutations of the pore region in KCNJ6
(600877), the human homolog, in 50 cases of Parkinson disease, 23 of
which were index cases of familial Parkinson disease.

Transgenic Drosophila expressing human alpha-synuclein carrying the
ala30-to-pro (A30P; 163890.0002) mutation faithfully replicate essential
features of human Parkinson disease, including age-dependent loss of
dopaminergic neurons, Lewy body-like inclusions, and locomotor
impairment. Scherzer et al. (2003) characterized expression of the
entire Drosophila genome at presymptomatic, early, and advanced disease
stages. Fifty-one signature transcripts were tightly associated with
A30P alpha-synuclein expression. At the presymptomatic stage, expression
changes revealed specific pathology. In age-matched transgenic
Drosophila expressing the arg406-to-trp mutation in tau (157140.0003),
the transcription of mutant alpha-synuclein-associated genes was normal,
suggesting highly distinct pathways of neurodegeneration.

Landau et al. (2005) found that Fas (TNFRSF6; 134637)-deficient
lymphoproliferative mice developed a PD phenotype, characterized by
extensive nigrostriatal degeneration accompanied by tremor, hypokinesia,
and loss of motor coordination, after treatment with MPTP at a dose that
caused no phenotype in wildtype mice. Mice with mutated Fasl (TNFSF6;
134638) and generalized lymphoproliferative disease had an intermediate
phenotype. Treatment of cultured midbrain neurons with Fasl to induce
Fas signaling protected them from MPTP toxicity. Mice lacking only Fas
exon 9, which encodes the death domain, but retaining the intracellular
Fas domain and cell surface expression of Fas, were resistant to MPTP.
Peripheral blood lymphocytes from patients with idiopathic PD showed a
highly significant deficit in their ability to upregulate Fas after
mitogen stimulation. Landau et al. (2005) concluded that reduced FAS
expression increases susceptibility to neurodegeneration and that FAS
has a role in neuroprotection.

- Therapeutic Strategies

Kordower et al. (2000) tested lentiviral vector delivery of glial cell
line-derived neurotrophic factor (GDNF; 600837), or lenti-GDNF, for its
trophic effects upon degenerating nigrostriatal neurons in nonhuman
primate models of Parkinson disease. The authors injected lenti-GDNF
into the striatum and substantia nigra of nonlesioned aged rhesus
monkeys or young adult rhesus monkeys treated 1 week prior with MPTP, a
neurotoxin known to specifically damage dopamine neurons. Extensive GDNF
expression with anterograde and retrograde transport was seen in all
animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In
MPTP-treated monkeys, lenti-GDNF reversed functional deficits and
completely prevented nigrostriatal degeneration. Additionally,
lenti-GDNF injections to intact rhesus monkeys revealed long-term gene
expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment
reversed motor deficits in a hand-reach task. Kordower et al. (2000)
concluded that GDNF delivery using a lentiviral vector system can
prevent nigrostriatal degeneration and induce regeneration in primate
models of PD and might be a viable therapeutic strategy for PD patients.

Luo et al. (2002) noted that a disinhibited and overactive subthalamic
nucleus (STN) alters basal ganglia network activity in PD, and that
electrical inhibition, pharmacologic silencing, and STN ablation can
improve the motor symptoms in PD, presumably by leading to suppression
of firing activity of neurons in the substantia nigra (SN). Using a
recombinant adeno-associated virus to transduce excitatory glutaminergic
neurons in the rat STN with glutamic acid decarboxylase (GAD), the
enzyme that catalyzes synthesis of the inhibitory neurotransmitter GABA,
Luo et al. (2002) showed that the neurons expressed the GAD gene and
changed from largely excitatory to predominantly inhibitory, resulting
in decreased excitatory and increased inhibitory response in the
substantia nigra. Moreover, the increased inhibitory tone provided
neuroprotection to the dopaminergic cells in response to toxic insult.
Rats with the transduced gene showed significant improvement from the
parkinsonian behavioral phenotype. Luo et al. (2002) emphasized the
plasticity in neurotransmission in the mammalian brain.

Teismann et al. (2003) showed that cyclooxygenase-2 (COX2; 600262), the
rate-limiting enzyme in prostaglandin E2 synthesis, is upregulated in
brain dopaminergic neurons of both PD and the MPTP mouse model of that
disorder. They demonstrated further that targeting COX2 does not protect
against MPTP-induced dopaminergic neurodegeneration by mitigating
inflammation. Instead, they provided evidence that COX2 inhibition
prevents the formation of the oxidant species of dopamine-quinone, which
has been implicated in the pathogenesis of PD. This study supported a
critical role for COX2 in both the pathogenesis and selectivity of the
PD neurodegenerative process. Because of the safety record of the COX2
inhibitors, and their ability to penetrate the blood-brain barrier,
these drugs may be therapies for PD.

The striatum is a major forebrain nucleus that integrates cortical and
thalamic afferents and forms the input nucleus of the basal ganglia.
Striatal projection neurons target the substantia nigra pars reticulata
(direct pathway) or the lateral globus pallidus (indirect pathway).
Kreitzer and Malenka (2007) showed that excitatory synapses onto
indirect-pathway medium spiny neurons exhibit higher release probability
and larger NMDA receptor currents than direct-pathway synapses.
Moreover, indirect-pathway medium spiny neurons selectively express
endocannabinoid-mediated long-term depression (eCB-LTD), which requires
dopamine D2 receptor (126450) activation. In models of Parkinson
disease, indirect-pathway eCB-LTD is absent but is rescued by a D2
receptor agonist or inhibitors of endocannabinoid degradation.
Administration of these drugs together in vivo in mice reduced
parkinsonian motor deficits, suggesting that endocannabinoid-mediated
depression of indirect-pathway synapses has a critical role in the
control of movement.

Kravitz et al. (2010) reported direct activation of basal ganglia
circuitry in vivo, using optogenetic control of direct- and
indirect-pathway medium spiny projection neurons, achieved through
Cre-dependent viral expression of channelrhodopsin-2 in the striatum of
BAC transgenic mice expressing Cre recombinase under control of
regulatory elements for the dopamine D1 (126449) or D2 receptors.
Bilateral excitation of indirect-pathway medium spiny projection neurons
elicited a parkinsonian state distinguished by increased freezing,
bradykinesia, and decreased locomotor initiations. In contrast,
activation of direct-pathway medium spiny projection neurons reduced
freezing and increased locomotion. In a mouse model of Parkinson
disease, activation of the direct pathway completely rescued deficits in
freezing, bradykinesia, and locomotor initiation. Kravitz et al. (2010)
concluded that their data establish a critical role for basal ganglia
circuitry in the bidirectional regulation of motor behavior and indicate
that modulation of direct-pathway circuitry may represent an effective
therapeutic strategy for ameliorating parkinsonian motor deficits.

Chan et al. (2007) found that dopamine-containing neurons in the
substantia nigra in mice relied on L-type voltage-gated calcium channels
(see, e.g., CACNA1S, 114208) to drive pacemaking. The reliance on these
calcium channels increased with age, and juvenile neurons tended to use
sodium-powered cation channels. The mechanism used by juvenile neurons
remained latent in adulthood, but pharmacologic (isradipine) or
gene-mediated blocking of the calcium channels in adult neurons induced
a reversion to the juvenile form of pacemaking. Such blocking of calcium
influx protected dopamine-containing neurons in both in vitro and in
vivo mouse models of Parkinson disease. The findings were consistent
with a theory of pathogenesis in which activity-dependent calcium influx
results in intracellular calcium accumulation that becomes toxic to
these neurons with age.

Sotnikova et al. (2006) developed a novel acute mouse model of severe
dopamine deficiency using Dat (SLC6A3; 126455)-null mice and
pharmacologic inhibition of tyrosine hydroxylase. Dopamine-deficient
Dat-null (DDD) mice demonstrated severe akinesia, rigidity, tremor, and
ptosis, similar to behaviors observed in patients with Parkinson
disease. Interestingly, DDD mice were able to swim in water, indicating
that certain movements and conditions can occur independently of
dopamine. Dopamine agonists such as L-dopa temporarily restored
locomotion in DDD mice, and amphetamine derivatives showed effectiveness
in reducing motor abnormalities in DDD mice. Sotnikova et al. (2006)
noted that the DDD mouse model provides a unique opportunity to screen
potential therapeutic agents for the treatment of Parkinson disease.

Berman et al. (2011) found that Slc1a1 (133550)-null mice developed
age-dependent progressive loss of dopaminergic neurons in the substantia
nigra, with more than 40% of these neurons lost by age 12 months, and
microglial activation in the substantia nigra. Mutant mice showed
impaired motor performance compared to wildtype mice. These features
were similar to those found in humans with Parkinson disease.
Dopaminergic neurons in the Slc1a1-null mice showed evidence of
increased oxidative stress. Long-term treatment of mutant mice with
N-acetylcysteine resulted in increased levels of glutathione, prevented
dopaminergic neuronal loss, and resulted in improved motor performance.
Berman et al. (2011) suggested that the Slc1a1-null mouse may be a
useful model for the chronic neuronal oxidative stress that occurs in
PD.

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Duvoisin (1986)
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83. Pankratz, N.; Nichols, W. C.; Uniacke, S. K.; Halter, C.; Rudolph,
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124-135, 2002.

84. Pankratz, N.; Wilk, J. B.; Latourelle, J. C.; DeStefano, A. L.;
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85. Parboosingh, J. S.; Rousseau, M.; Rogan, F.; Amit, Z.; Chertkow,
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*FIELD* CS
INHERITANCE:
Isolated cases;
Multifactorial

HEAD AND NECK:
[Face];
Masked facies;
[Nose];
Decreased sense of smell

GENITOURINARY:
[Bladder];
Urinary urgency

ABDOMEN:
[Gastrointestinal];
Dysphagia;
Constipation

NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Bradykinesia;
Rigidity;
Postural instability;
Resting tremor;
Micrographia;
Gait disturbances;
Shuffling gait;
Dystonia;
Dysarthria;
Monotonous speech;
Dysautonomia may occur;
Visual hallucinations may occur;
Dementia may occur;
Sleep disturbances;
Neuronal loss and gliosis in the substantia nigra pars compacta;
Loss of dopaminergic neurons;
Intracellular Lewy bodies;
Aggregation of SNCA-immunopositive inclusions;
[Behavioral/psychiatric manifestations];
Depression

MISCELLANEOUS:
Onset mid to late adulthood;
Insidious onset;
Progressive disorder;
Levodopa-responsive

*FIELD* CN
Cassandra L. Kniffin - revised: 11/15/2010

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 06/27/2012
ckniffin: 11/15/2010

*FIELD* CN
Ada Hamosh - updated: 12/06/2013
Cassandra L. Kniffin - updated: 3/7/2013
Cassandra L. Kniffin - updated: 12/4/2012
Cassandra L. Kniffin - updated: 3/21/2012
Cassandra L. Kniffin - updated: 9/6/2011
Cassandra L. Kniffin - updated: 6/23/2011
Cassandra L. Kniffin - updated: 3/24/2011
Cassandra L. Kniffin - updated: 11/2/2010
Cassandra L. Kniffin - updated: 9/17/2010
Ada Hamosh - updated: 8/24/2010
Cassandra L. Kniffin - updated: 6/25/2010
Cassandra L. Kniffin - updated: 5/6/2010
Cassandra L. Kniffin - updated: 3/1/2010
Cassandra L. Kniffin - updated: 2/19/2010
Cassandra L. Kniffin - updated: 11/4/2009
Cassandra L. Kniffin - updated: 10/22/2009
Ada Hamosh - updated: 8/25/2009
Cassandra L. Kniffin - updated: 2/3/2009
Cassandra L. Kniffin - updated: 10/8/2008
Cassandra L. Kniffin - updated: 4/2/2008
Victor A. McKusick - updated: 3/31/2008
Cassandra L. Kniffin - updated: 2/5/2008
Cassandra L. Kniffin - updated: 11/13/2007
Cassandra L. Kniffin - updated: 10/2/2007
Cassandra L. Kniffin - updated: 9/11/2007
Ada Hamosh - updated: 8/17/2007
Cassandra L. Kniffin - updated: 7/17/2007
Ada Hamosh - updated: 2/27/2007
Cassandra L. Kniffin - updated: 2/19/2007
Ada Hamosh - updated: 11/28/2006
Victor A. McKusick - updated: 6/1/2006
Cassandra L. Kniffin - updated: 5/24/2006
Cassandra L. Kniffin - updated: 5/15/2006
Cassandra L. Kniffin - updated: 4/20/2006
Paul J. Converse - updated: 4/5/2006
George E. Tiller - updated: 1/10/2006
Victor A. McKusick - updated: 10/14/2005
George E. Tiller - updated: 10/3/2005
George E. Tiller - updated: 9/12/2005
Cassandra L. Kniffin - updated: 8/26/2005
Ada Hamosh - updated: 7/20/2005
Cassandra L. Kniffin - updated: 4/18/2005
Victor A. McKusick - updated: 11/15/2004
George E. Tiller - updated: 10/27/2004
George E. Tiller - updated: 2/16/2004
Cassandra L. Kniffin - updated: 1/5/2004
Cassandra L. Kniffin - updated: 10/31/2003
Victor A. McKusick - updated: 6/13/2003
Cassandra L. Kniffin - updated: 5/28/2003
Ada Hamosh - updated: 5/9/2003
Victor A. McKusick - updated: 4/11/2003
Victor A. McKusick - updated: 4/9/2003
Ada Hamosh - updated: 3/31/2003
Cassandra L. Kniffin - reorganized: 10/29/2002
Cassandra L. Kniffin - updated: 10/11/2002
Victor A. McKusick - updated: 9/12/2002
Cassandra L. Kniffin - updated: 7/29/2002
Victor A. McKusick - updated: 6/4/2002
Victor A. McKusick - updated: 5/22/2002
Victor A. McKusick - updated: 4/8/2002
Ada Hamosh - updated: 2/6/2002
Victor A. McKusick - updated: 9/27/2001
Victor A. McKusick - updated: 6/26/2001
Victor A. McKusick - updated: 1/4/2001
Ada Hamosh - updated: 11/7/2000
Ada Hamosh - updated: 7/13/2000
Victor A. McKusick - updated: 12/22/1999
Orest Hurko - updated: 6/14/1999
Victor A. McKusick - updated: 12/30/1998
Victor A. McKusick - updated: 4/7/1998
Victor A. McKusick - updated: 2/11/1998
Victor A. McKusick - updated: 9/5/1997
Victor A. McKusick - updated: 6/27/1997
Victor A. McKusick - updated: 3/12/1997
Orest Hurko - updated: 11/6/1996
Orest Hurko - updated: 11/5/1996
Orest Hurko - updated: 4/1/1996
Orest Hurko - updated: 3/6/1996
Orest Hurko - updated: 2/5/1996
Orest Hurko - updated: 11/16/1995

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 12/06/2013
carol: 11/21/2013
ckniffin: 11/19/2013
carol: 4/1/2013
carol: 3/12/2013
ckniffin: 3/7/2013
alopez: 12/13/2012
carol: 12/5/2012
ckniffin: 12/4/2012
terry: 9/25/2012
terry: 8/8/2012
terry: 6/4/2012
terry: 5/17/2012
terry: 4/10/2012
carol: 3/22/2012
ckniffin: 3/21/2012
terry: 10/10/2011
carol: 10/3/2011
ckniffin: 10/3/2011
carol: 9/6/2011
ckniffin: 9/6/2011
ckniffin: 9/1/2011
wwang: 6/29/2011
ckniffin: 6/23/2011
wwang: 4/13/2011
wwang: 4/12/2011
ckniffin: 3/24/2011
carol: 1/28/2011
ckniffin: 11/17/2010
alopez: 11/10/2010
wwang: 11/2/2010
wwang: 9/23/2010
ckniffin: 9/17/2010
mgross: 8/24/2010
terry: 8/24/2010
wwang: 8/4/2010
wwang: 7/14/2010
ckniffin: 6/25/2010
carol: 5/25/2010
wwang: 5/10/2010
ckniffin: 5/6/2010
wwang: 3/4/2010
ckniffin: 3/1/2010
wwang: 2/19/2010
ckniffin: 2/19/2010
alopez: 1/4/2010
wwang: 12/28/2009
terry: 12/1/2009
carol: 11/11/2009
ckniffin: 11/4/2009
wwang: 10/30/2009
ckniffin: 10/22/2009
carol: 9/4/2009
alopez: 9/1/2009
terry: 8/25/2009
wwang: 2/9/2009
terry: 2/6/2009
ckniffin: 2/3/2009
ckniffin: 10/17/2008
wwang: 10/15/2008
ckniffin: 10/8/2008
carol: 9/29/2008
ckniffin: 9/29/2008
carol: 9/25/2008
mgross: 7/17/2008
ckniffin: 4/30/2008
wwang: 4/10/2008
ckniffin: 4/2/2008
alopez: 4/1/2008
terry: 3/31/2008
wwang: 2/11/2008
ckniffin: 2/5/2008
wwang: 2/4/2008
ckniffin: 11/13/2007
alopez: 11/7/2007
wwang: 10/8/2007
ckniffin: 10/2/2007
wwang: 9/12/2007
ckniffin: 9/11/2007
carol: 8/17/2007
ckniffin: 7/17/2007
alopez: 3/8/2007
terry: 2/27/2007
wwang: 2/22/2007
ckniffin: 2/19/2007
alopez: 12/7/2006
terry: 11/28/2006
alopez: 8/4/2006
alopez: 6/1/2006
wwang: 5/24/2006
ckniffin: 5/24/2006
ckniffin: 5/15/2006
wwang: 4/26/2006
ckniffin: 4/20/2006
mgross: 4/5/2006
wwang: 2/15/2006
terry: 1/10/2006
terry: 12/21/2005
alopez: 10/18/2005
alopez: 10/17/2005
terry: 10/14/2005
wwang: 10/4/2005
alopez: 10/3/2005
terry: 9/12/2005
wwang: 9/6/2005
ckniffin: 8/26/2005
alopez: 7/20/2005
terry: 7/20/2005
wwang: 5/3/2005
ckniffin: 4/18/2005
carol: 4/18/2005
tkritzer: 11/18/2004
terry: 11/15/2004
tkritzer: 10/27/2004
carol: 9/21/2004
alopez: 6/17/2004
cwells: 2/16/2004
tkritzer: 1/7/2004
ckniffin: 1/5/2004
carol: 11/11/2003
tkritzer: 11/6/2003
ckniffin: 10/31/2003
tkritzer: 9/17/2003
tkritzer: 9/15/2003
alopez: 6/23/2003
terry: 6/13/2003
carol: 6/6/2003
carol: 5/28/2003
ckniffin: 5/27/2003
alopez: 5/16/2003
cwells: 5/12/2003
terry: 5/9/2003
ckniffin: 4/15/2003
carol: 4/14/2003
terry: 4/11/2003
carol: 4/9/2003
terry: 4/9/2003
alopez: 4/1/2003
terry: 3/31/2003
carol: 1/16/2003
carol: 10/29/2002
ckniffin: 10/17/2002
carol: 10/14/2002
ckniffin: 10/11/2002
carol: 9/19/2002
tkritzer: 9/12/2002
carol: 9/9/2002
carol: 8/7/2002
ckniffin: 7/29/2002
alopez: 6/13/2002
alopez: 6/12/2002
cwells: 6/12/2002
terry: 6/4/2002
cwells: 6/4/2002
cwells: 6/3/2002
terry: 5/22/2002
cwells: 4/19/2002
carol: 4/19/2002
cwells: 4/17/2002
terry: 4/8/2002
carol: 4/2/2002
alopez: 2/7/2002
terry: 2/6/2002
alopez: 9/28/2001
terry: 9/27/2001
mcapotos: 7/2/2001
mcapotos: 6/28/2001
terry: 6/26/2001
mgross: 5/18/2001
cwells: 1/11/2001
cwells: 1/10/2001
terry: 1/4/2001
carol: 11/17/2000
mgross: 11/7/2000
terry: 11/7/2000
carol: 11/6/2000
terry: 10/6/2000
alopez: 7/13/2000
mcapotos: 1/4/2000
terry: 12/22/1999
carol: 6/14/1999
carol: 1/4/1999
terry: 12/30/1998
carol: 11/23/1998
carol: 6/10/1998
carol: 5/2/1998
terry: 4/7/1998
alopez: 2/11/1998
dholmes: 2/6/1998
terry: 9/12/1997
terry: 9/5/1997
alopez: 7/7/1997
mark: 6/27/1997
terry: 6/27/1997
terry: 3/12/1997
terry: 3/6/1997
terry: 2/10/1997
mark: 1/6/1997
mark: 11/15/1996
terry: 11/15/1996
mark: 11/6/1996
terry: 10/22/1996
terry: 4/15/1996
mark: 4/2/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 3/6/1996
terry: 2/29/1996
mark: 2/5/1996
terry: 1/31/1996
mark: 9/13/1995
terry: 7/28/1995
mimadm: 3/25/1995
carol: 1/19/1995
jason: 6/27/1994

MIM 602533
*RECORD*
*FIELD* NO
602533
*FIELD* TI
*602533 ONCOGENE DJ1; DJ1
;;PARK7 GENE; PARK7
*FIELD* TX

DESCRIPTION

DJ1, or PARK7, has pleiotropic function that includes roles as a
read morechaperone with protease activity, a transcriptional regulator, and an
antioxidant scavenger and redox sensor. DJ1 is also involved in
tumorigenesis and in maintaining mitochondrial homeostasis (summary by
Ottolini et al., 2013).

CLONING

Nagakubo et al. (1997) used yeast 2-hybrid screening of a HeLa cell
library to clone a cDNA that encodes a novel 189-amino acid protein,
termed DJ1. Northern blot analysis revealed that DJ1 is ubiquitously
expressed as a 1.0-kb transcript. Western blot analysis and
immunofluorescence showed that the DJ1 protein is present in both nuclei
and cytoplasm of HeLa cells. After addition of serum to cells, DJ1
expression increased and the protein translocated from the cytoplasm to
nuclei. A search of the GenBank protein database revealed that DJ1 has
approximately 40% identity to the 198-amino acid protein product of the
E. coli thiazole monophosphate biosynthesis (ThiJ) gene. A homolog also
exists in the nematode C. elegans.

Northern blot analysis by Bonifati et al. (2003) showed ubiquitous
expression of the DJ1 transcript, particularly in liver, skeletal
muscle, and kidney. In the brain, expression was also ubiquitous, with
higher levels of the transcript in subcortical regions, such as the
caudate nucleus, the thalamus, the substantia nigra, and the
hippocampus, that are more affected in parkinson disease (see MOLECULAR
GENETICS).

Zhang et al. (2005) generated highly specific antibodies to DJ1 protein
and investigated the subcellular localization of endogenous DJ1 protein
in both mouse brain tissues and human neuroblastoma cells. DJ1 was
widely distributed and was highly expressed in brain. Cell fractionation
and immunogold electron microscopy revealed an endogenous pool of DJ1 in
mitochondrial matrix and intermembrane space.

By screening a rat testis cDNA library, Wagenfeld et al. (1998) cloned a
homologous gene in rats, called contraception associated protein-1
(CAP1), encoding a deduced protein that shares 95% and 91% sequence
homology to mouse and human DJ1, respectively. A 1.6-kb transcript was
detected in all rat tissues examined, with the highest level of
expression in the testis.

GENE STRUCTURE

Bonifati et al. (2003) reported that the DJ1 gene contains 8 exons
spanning 24 kb. The first 2 exons (1A and 1B) are noncoding and
alternatively spliced.

MAPPING

By genomic sequence analysis, Bonifati et al. (2003) mapped the DJ1 gene
to chromosome 1p36.

BIOCHEMICAL FEATURES

Wilson et al. (2003) reported the 3-dimensional structure of the DJ1
protein, determined at a resolution of 1.1 angstroms by x-ray
crystallography. A highly conserved cysteine residue, which is
catalytically essential in homologs of human DJ1, showed an extreme
sensitivity to radiation damage and may be subject to other forms of
oxidative modification as well. The structure suggested that the loss of
function caused by the Parkinson-associated mutation L166P (602533.0002)
is due to destabilization of the dimer interface. Taken together, the
crystal structure of human DJ1 plus other observations suggested the
possible involvement of this protein in the cellular oxidative stress
response and a general etiology of neurodegenerative diseases. Cookson
(2003) commented.

Macedo et al. (2003) demonstrated that DJ1 protein formed a dimeric
structure under physiologic conditions. Conversely, the L166P mutant
protein showed a different elution profile in gel filtration assays as
compared with wildtype, suggesting that L166P might form higher-order
protein structures. In lymphoblasts from a parkinsonian patient who
carried the homozygous mutation, the level of mutant protein was very
low as compared with wildtype protein. Transfection experiments
indicated that the mutant protein was rapidly degraded. Macedo et al.
(2003) proposed that the rapid turnover and structural changes of the
L166P mutant protein may be crucial in disease pathogenesis.

Chen et al. (2010) reported that DJ1 is synthesized as a latent protease
zymogen with low intrinsic proteolytic activity. DJ1 protease zymogen
was activated by the removal of a 15-amino acid peptide at its C
terminus. The activated DJ1 functioned as a cysteine protease with
cys106 and his126 as the catalytic diad. Endogenous DJ1 in dopaminergic
cells underwent C-terminal cleavage in response to mild oxidative
stress, suggesting that DJ1 protease activation occurs in a
redox-dependent manner. Moreover, the C-terminally cleaved form of DJ1
with activated protease function exhibited enhanced cytoprotective
action against oxidative stress-induced apoptosis. The cytoprotective
action of DJ1 was abolished by C106A and H126A mutations. Chen et al.
(2010) proposed a role for DJ1 protease in cellular defense against
oxidative stress.

GENE FUNCTION

Nagakubo et al. (1997) found that the DJ1 gene has weak transforming
ability in NIH 3T3 cells, but transformation by DJ1 is synergistically
enhanced by cotransfection with HRAS (190020) or MYC (190080).

Takahashi et al. (2001) showed that DJ1 bound strongly to PIASx-alpha
(603567), a modulator of the nuclear androgen receptor (AR; 313700), and
colocalized with PIASx-alpha in the nuclei of monkey Cos-I cells. While
PIASx repressed AR transcriptional activity to 40% of the original
level, as measured with an androgen responsive element-luciferase
reporter, addition of DJ1 abrogated this suppression. Furthermore, DJ1
bound to the AR-interacting domain of PIASx, suggesting that DJ1
antagonized PIASx function by absorbing it and interfering with its
binding to AR. Takahashi et al. (2001) concluded that, in somatic cells,
DJ1 functions as a positive regulator of AR.

Rizzu et al. (2004) presented evidence suggesting that DJ1 colocalizes
within a subset of pathologic tau (MAPT; 157140) inclusions in a diverse
group of neurodegenerative disorders known as tauopathies, and that the
solubility of DJ1 is altered in association with its aggregation within
these inclusions.

Moore et al. (2005) showed that pathogenic mutant forms of DJ1
specifically but differentially associate with parkin (602544), an E3
ubiquitin ligase. Chemical crosslinking showed that pathogenic DJ1
mutants exhibited impairment in homodimer formation, suggesting that
parkin may bind to monomeric DJ1. Parkin failed to specifically
ubiquitinate and enhance the degradation of L166P (602533.0002) and M26I
(602533.0003) mutant DJ1, but instead promoted their stability in
cultured cells. Oxidative stress also promoted an interaction between
DJ1 and parkin, but this did not result in the ubiquitination or
degradation of DJ1. DJ1 levels were increased in the insoluble fraction
of sporadic PD/DLB brains, but were reduced in the insoluble fraction of
parkin-linked autosomal recessive juvenile-onset PD brains. The authors
proposed that DJ1 and parkin may be linked in a common molecular pathway
at multiple levels.

In human dopaminergic neuronal cells, Xu et al. (2005) showed that the
major interacting proteins with DJ1 were NRB54 (NONO; 300084) and PSF
(SFPQ; 605119), which are multifunctional regulators of transcription
and RNA metabolism. PD-associated DJ1 mutants exhibited decreased
nuclear distribution and increased mitochondrial localization, resulting
in diminished colocalization with coactivator NRB54 and repressor PSF.
Wildtype DJ1 inhibited the transcriptional silencing activity of PSF
unlike DJ1 mutants, and PSF induced neuronal apoptosis, which was
reversed by wildtype DJ1 and to a lesser extent by PD-associated DJ1
mutants. RNAi-knockdown of DJ1 sensitized cells to PSF-induced
apoptosis. Both DJ1 and NRB54 blocked oxidative stress and mutant
alpha-synuclein (SNCA; 163890)-induced cell death. The findings showed
that DJ1 is a neuroprotective transcriptional coactivator that may act
in concert with NRB54 and PSF to regulate the expression of a
neuroprotective genetic program. Xu et al. (2005) concluded that DJ1
mutations that impair transcriptional coactivator function can render
dopaminergic neurons vulnerable to apoptosis and may contribute to the
pathogenesis of Parkinson disease (168600).

Junn et al. (2005) found that DJ1 overexpression in a human dopaminergic
neuroblastoma cell line afforded modest protection against oxidative
stress-induced cell death. A more robust cytoprotection was afforded by
interaction of overexpressed DJ1 with the death protein DAXX (603186).
DJ1 sequestered DAXX in the nucleus and prevented its translocation to
the cytoplasm, where DAXX would normally activate its effector kinase,
ASK1 (MAP3K5; 602448), to trigger the death pathway. DJ1 carrying the
L166P mutation did not interact with DAXX and was unable to protect
cells from oxidative damage or DAXX/ASK1-induced apoptosis.

Meulener et al. (2006) found that human DJ1 could rescue Drosophila
lacking Dj1b, the fly homolog of DJ1, from oxidative insult, and that a
conserved cysteine (cys104, which is analogous to human cys106) was
critical for antioxidant function in vivo. SDS-PAGE analysis showed that
DJ1 modification increased with age in flies, mice, and humans. In
particular, an increase in acidic DJ1 isoforms with lower activity was
observed. Modification of Dj1b increased dramatically in aged flies upon
oxidative insult, and aged flies were more vulnerable to oxidative
stress. Meulener et al. (2006) concluded that the risk factors of age
and oxidative stress may regulate DJ1 protein activity, potentially
contributing to Parkinson disease.

Using small-interfering RNA (siRNA) to disrupt DJ1 expression in a human
nonsmall cell lung carcinoma cell line, Clements et al. (2006) showed
that DJ1 was required for the expression of several genes, including the
NRF2 (NFE2L2; 600492)-regulated antioxidant enzyme NQO1 (125860).
Without DJ1, NRF2 protein was unstable, and transcriptional responses
were decreased both basally and after induction. DJ1 was indispensable
for NRF2 stabilization by affecting NRF2 association with KEAP1
(606016), an inhibitor protein that promotes ubiquitination and
degradation of NRF2.

In human dopaminergic cells, Tang et al. (2006) demonstrated that
wildtype DJ1 and PINK1 (608309), mutation in which causes PARK6
(605909), coimmunoprecipitate and interact functionally to protect cells
from toxic oxidative MPP-induced cell death. Overexpression of both
proteins resulted in a synergistic protective effect, and mutations in
both proteins resulted in increased cell death compared to either mutant
protein alone, suggesting a common mechanism. Evidence also suggested
that DJ1 helps to stabilize PINK1.

Xiong et al. (2009) demonstrated that parkin, PINK1, and DJ1 interact
and form an approximately 200-kD functional ubiquitin E3 ligase complex
in human primary neurons. PINK1 was shown to increase the activity of
parkin, which degrades itself via the ubiquitin-proteasome system.
Pathogenic PINK1 (G309D; 608309.0001) did not promote ubiquitination and
degradation of parkin or the parkin substrate synphilin-1 (603779) in
transfected cells. Expression of DJ1 increased PINK1 expression, perhaps
acting as a stabilizer. Overexpression of parkin substrates or heat
shock treatment resulted in parkin accumulation in Pink1- or
Dj1-deficient murine cells, and pathogenic parkin mutations resulted in
a reduced ability to promote degradation of parkin substrates, all
suggesting a decrease in E3 ubiquitin activity. Xiong et al. (2009)
suggested that this complex promotes degradation of un- or misfolded
proteins, including parkin, and that disruption of the activity of this
complex leads to accumulation of abnormal proteins and increased
susceptibility to oxidative stress, which is toxic to neurons and may
lead to Parkinson disease.

Using Dj1 -/- mouse cells, DJ1-linked PD patient lymphoblasts, and
DJ1-knockdown human cell lines with appropriate controls, Irrcher et al.
(2010) showed that loss of DJ1 resulted in mitochondrial fragmentation
and sensitivity to oxidative damage. Reactive oxygen species (ROS)
appeared to play a critical role in the defects, as mitochondria
isolated from Dj1 -/- animals produced more ROS than controls and ROS
scavengers rescued the phenotype. The aberrant mitochondrial phenotype
was also reversed by expression of either wildtype human parkin or PINK.
Dj1 -/- mouse cells and DJ1-linked PD patient lymphoblasts showed
evidence of elevated autophagy, but not mitophagy.

Ottolini et al. (2013) found that DJ1 was expressed at
mitochondrial-associated membranes in the endoplasmic reticulum (ER) and
that DJ1 maintained mitochondrial morphology and influenced
mitochondrial Ca(2+) transients in stimulated HeLa cells. Knockdown of
DJ1 resulted in mitochondrial fragmentation and decreased mitochondrial
Ca(2+) uptake from the ER following stimulation. Conversely,
overexpression of DJ1 augmented stimulation-induced mitochondrial Ca(2+)
transients by increasing ER-mitochondrial communication. Overexpression
of p53 in HeLa cells impaired the ability of mitochondria to accumulate
Ca(2+) following stimulation, disrupted mitochondrial morphology, and
reduced mitochondria-ER contact sites. DJ1 overexpression prevented p53
effects and reestablished ER-mitochondrial contacts. The effects of p53
on mitochondria did not require the transcriptional regulatory function
of p53. Rescue of mitochondria by DJ1 was associated with enhanced
degradation of p53, but it did not require DJ1 upregulation or DJ1
kinase activity. Overexpression of the mitochondrial profusion protein
mitofusin-2 (MFN2; 608507) also reversed the effects of p53 on
mitochondria. Ottolini et al. (2013) concluded that DJ1 has a direct
role in ER-mitochondria coupling and is essential to maintain
mitochondrial structure and function.

Bjorkblom et al. (2013) found that recombinant human DJ1 bound copper,
mercury, and, more weakly, manganese, but not other ions tested. Dj1
also protected mouse embryonic fibroblasts (MEFs) against copper- and
mercury-induced cytotoxicity. Exposure of MEFs to a nontoxic
concentration of dopamine, together with copper or mercury, resulted in
an almost immediate and dramatic surge of intracellular oxidation. The
oxidative response was exacerbated in Dj1 -/- MEFs.

MOLECULAR GENETICS

In 2 consanguineous families from genetically isolated communities in
the Netherlands and Italy with autosomal recessive early-onset Parkinson
disease (PARK7; 606324), Bonifati et al. (2003) identified 2 mutations
in the DJ1 gene that cosegregated with the disease (602533.0001 and
602533.0002).

Among 185 unrelated patients with early-onset Parkinson disease,
Abou-Sleiman et al. (2003) identified 2 patients with mutations in the
DJ1 gene (602533.0003-602533.0004); one was homozygous and the other was
heterozygous. In addition, several variants were found in the DJ1 gene,
which likely represented polymorphisms. The authors estimated that the
frequency of DJ1 mutations in early-onset Parkinson disease is very low,
at approximately 1%. No mutations in the DJ1 gene were identified in a
cohort of later-onset sporadic cases of Parkinson disease.

In a series of in vitro studies, Takahashi-Niki et al. (2004) found that
mutant DJ1 proteins M26I (602533.0003), D149A (602533.0004), and L166P
(602533.0002) formed heterodimers with wildtype DJ1. Mutant proteins
M26I and L166P were unstable and were degraded by the proteasome system.
Cell lines expressing the mutant M26I and L166P proteins showed reduced
ability to eliminate exogenous hydrogen peroxide, indicating increased
susceptibility to oxidative stress. In contrast, the mutant D149A
protein showed increased stability compared to wildtype, and cells
expressing the mutant D149A were resistant to hydrogen peroxide-induced
cell death.

Zhang et al. (2005) generated human neuroblastoma cells stably
transfected with wildtype or mutant (e.g., M26I, L166P, and D149A) DJ1
constructs and performed mitochondrial fractionation and confocal
colocalization imaging studies. When compared with wildtype and other
mutants, the L166P mutant exhibited a largely reduced protein level.
However, the pathogenic mutations did not alter the distribution of DJ1
to mitochondria. Zhang et al. (2005) concluded that DJ1 is an integral
mitochondrial protein that may have important functions in regulating
mitochondrial physiology.

ANIMAL MODEL

Kim et al. (2005) found that mice with a targeted deletion of the Dj1
gene developed normally, had normal numbers of dopaminergic neurons in
the substantia nigra, and showed no abnormal gross motor behavior up to
13 months of age. In vitro studies showed that primary cortical neurons
from the Dj1-null mice exhibited increased sensitivity to oxidative
stress compared to control cells. After challenge with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), Dj1-null mice
showed a significant decrease in total activity and a greater loss of
striatal dopaminergic neurons compared to control mice. Restoration of
Dj1 expression in cell cultures or in Dj1-null mice resulted in a
protective effect. Moreover, wildtype mice that received adenoviral
delivery of Dj1 showed some resistance to MPTP-induced neuronal damage.
Kim et al. (2005) concluded that Dj1 protects against neuronal oxidative
stress, and that while loss of Dj1 alone may not be sufficient to
produce parkinsonism, it may confer hypersensitivity to dopaminergic
insults when challenged.

In vitro and in vivo, Aleyasin et al. (2007) found that Dj1-null mice
were significantly more susceptible to glutamate-induced neuronal
excitotoxicity compared to controls. Expression of Dj1 provided
protection. Further studies showed that the oxidation-sensitive cys106
residue was essential for neuronal protection from excitotoxicity. Dj1
expression decreased markers of oxidative stress after stroke insult in
vivo, suggesting that Dj1 protects through alleviation of oxidative
stress. Aleyasin et al. (2007) suggested that Dj1 may be important in
other neuropathologic conditions besides Parkinson disease, and noted
commonalities among different neuropathologies.

Andres-Mateos et al. (2007) found that mice with targeted deletion of
Dj1 exons 2 and 3 had no significant changes in the striatal
dopaminergic system compared to wildtype mice. However, mitochondria
isolated from the mutant mice contained a 2-fold increase in hydrogen
peroxide associated with a decrease in mitochondrial aconitase (ACO2;
100850). Older mutant mice showed a compensatory upregulation of
mitochondrial superoxide dismutase (SOD1; 147450) and glutathione
peroxidase activity (see, e.g., GPX1; 138320). Functional studies and
mass spectrometry indicated that DJ1 is an atypical peroxiredoxin-like
peroxidase that scavenges hydrogen peroxide through oxidation of cys106.

Using transgenic mice that expressed a redox-sensitive variant of green
fluorescent protein targeted to the mitochondrial matrix, Guzman et al.
(2010) showed that the engagement of plasma membrane L-type calcium
channels during normal autonomous pacemaking created an oxidant stress
that was specific to vulnerable substantia nigra pars compacta (SNc)
dopaminergic neurons. The oxidant stress engaged defenses that induced
transient, mild mitochondrial depolarization or uncoupling. The mild
uncoupling was not affected by deletion of cyclophilin D (601753), which
is a component of the permeability transition pore, but was attenuated
by genipin and purine nucleotides, which are antagonists of cloned
uncoupling proteins. Knocking out DJ1 downregulated the expression of 2
uncoupling proteins, UCP4 (SLC25A27) and UCP5 (SLC25A14; 300242),
compromised calcium-induced uncoupling, and increased oxidation of
matrix proteins specifically in SNc dopaminergic neurons. Because drugs
approved for human use can antagonize calcium entry through L-type
channels, Guzman et al. (2010) suggested that their results pointed to a
novel neuroprotective strategy for both idiopathic and familial forms of
Parkinson disease (168600).

*FIELD* AV
.0001
PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET
PARK7, 14-KB DEL

In a consanguineous Dutch family with early-onset Parkinson disease
(PARK7; 606324), Bonifati et al. (2003) identified a 14-kb homozygous
deletion in the DJ1 gene, which deleted exons 1 through 5 and 4 kb of
sequence upstream of the open reading frame start. The deletion showed
cosegregation with the disease in the 4 affected family members and was
absent in over 1,220 chromosomes from the Dutch population.

Irrcher et al. (2010) showed that this deletion mutation in DJ1 resulted
in fragmented mitochondria and elevated markers of autophagy.

.0002
PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET
PARK7, LEU166PRO

In a consanguineous Italian family with autosomal recessive early-onset
Parkinson disease (PARK7; 606324), Bonifati et al. (2003) identified a
homozygous 497T-C transition in the DJ1 gene, resulting in a
leu166-to-pro substitution (L166P) in the protein. The mutation showed
cosegregation with the disease in 3 affected sibs and was absent in 320
chromosomes from the Italian population. A molecular model of the
mutation was predicted to destabilize the terminal helix of the protein.

Irrcher et al. (2010) showed that the L166P mutation in DJ1 resulted in
fragmented mitochondria and elevated markers of autophagy.

.0003
PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET
PARK7, MET26ILE

In an Ashkenazi Jewish patient with early-onset Parkinson disease
(606324), Abou-Sleiman et al. (2003) identified a homozygous A-to-G
change in exon 2 of the DJ1 gene, resulting in a met26-to-ile (M26I)
substitution. The mutation was not present in more than 1,000 control
chromosomes.

.0004
PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET
PARK7, ASP149ALA

In an Afro-Caribbean patient with early-onset Parkinson disease
(606324), Abou-Sleiman et al. (2003) identified a heterozygous mutation
in exon 4 of the DJ1 gene, resulting in an asp149-to-ala (D149A)
substitution. The mutation was not found in 750 white, 160 Ashkenazi, or
40 Afro-Caribbean chromosomes tested, suggesting that it is pathogenic,
but the authors noted that they did not identify a second mutation in
the DJ1 gene in this patient.

Bjorkblom et al. (2013) found that DJ1 with the D149A substitution bound
copper with higher affinity than wildtype DJ1. Mutant DJ1 also bound
mercury. However, in contrast with wildtype DJ1, mutant Dj1 lacked the
ability to protect mouse embryonic fibroblasts from copper- and
mercury-induced cytotoxicity.

.0005
PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET
PARK7, GLU64ASP

Analyzing the DJ1 gene in 104 patients with early-onset Parkinson
disease (606324), Hering et al. (2004) identified a homozygous 192G-C
transversion, resulting in a glu64-to-asp (E64D) substitution, in 1
patient of Turkish ancestry. In the proband, a substantial reduction of
dopamine uptake transporter (DAT; 126455) binding was found in the
striatum by PET scan, indicating a serious loss of presynaptic
dopaminergic afferents. The proband's sister, also homozygous for E64D,
was clinically unaffected but showed reduced dopamine uptake when
compared with a clinically unaffected brother, who was heterozygous for
E64D. By crystallography, Hering et al. (2004) demonstrated that the
E64D mutation does not alter the structure of the DJ1 protein; however,
they observed a tendency toward decreased levels of the mutant protein
when overexpressed in HEK293 or COS-7 cells. By immunocytochemistry,
about 5% of the cells expressing E64D and up to 80% of the cells
expressing the L166P mutation (602533.0002) displayed a predominant
nuclear localization of the mutant DJ1 protein, in contrast to the
homogeneous nuclear and cytoplasmic staining in HEK293 cells
overexpressing wildtype DJ1.

.0006
PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET
PARK7, GLU163LYS AND 18-BP DUP

In 3 affected sibs from a consanguineous southern Italian family with
early-onset parkinsonism (606324), Annesi et al. (2005) identified
double homozygosity for mutations in the DJ1 gene. One was a 3385G-A
transition in exon 7, resulting in a glu163-to-lys (E163K) substitution,
and the other was an 18-bp duplication (168-185dup) in the promoter
region. Age at disease onset was 36, 35, and 24 years, respectively.
Severe amyotrophic lateral sclerosis and cognitive impairment were
prominent in 1 sib, while the other 2 had prominent parkinsonism and
behavioral abnormalities.

.0007
PARKINSON DISEASE, AUTOSOMAL RECESSIVE EARLY-ONSET, DIGENIC, PINK1/DJ1
PARK7, ALA39SER

In 2 Chinese sibs with early-onset Parkinson disease (see 605909), Tang
et al. (2006) identified compound heterozygosity for 2 mutations in 2
different genes: a 115G-T transversion in exon 3 of the DJ1 gene
resulting in an ala39-to-ser (A39S) substitution in the third beta-sheet
of the protein, and a P399L mutation (608309.0014) in the predicted
kinase domain of the PINK1 gene. The DJ1 and PINK1 mutations were not
observed in 240 and 568 control chromosomes, respectively, and both were
located in highly conserved residues. The findings were consistent with
digenic inheritance of Parkinson disease. A 42-year-old unaffected
family member also carried both mutations, suggesting incomplete
penetrance. Coimmunoprecipitation studies showed that both wildtype and
mutant PINK1 interacted with both wildtype and mutant DJ1. Expression of
wildtype DJ1 increased steady-state levels of both mutant and wildtype
PINK1, but mutant DJ1 decreased steady-state levels of both mutant and
wildtype PINK1, suggesting that wildtype DJ1 can enhance PINK1
stability. Human neuroblastoma cells expressing either mutant PINK1 or
DJ1 showed reduced viability following oxidative challenge with MPP
compared to control cells, indicating that both proteins protect against
cell stress. Coexpression of both wildtype proteins resulted in a
synergistic increase in cell viability against MPP-induced stress. In
addition, coexpression of both mutant proteins significantly increased
susceptibility of cells to death, compared to either mutant alone. These
findings indicated that DJ1 and PINK1 function collaboratively.

*FIELD* RF
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N. W.: The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann.
Neurol. 54: 283-286, 2003.

2. Aleyasin, H.; Rousseaux, M. W. C.; Phillips, M.; Kim, R. H.; Bland,
R. J.; Callaghan, S.; Slack, R. S.; During, M. J.; Mak, T. W.; Park,
D. S.: The Parkinson's disease gene DJ-1 is also a key regulator
of stroke-induced damage. Proc. Nat. Acad. Sci. 104: 18748-18753,
2007.

3. Andres-Mateos, E.; Perier, C.; Zhang, L.; Blanchard-Fillion, B.;
Greco, T. M.; Thomas, B.; Ko, H. S.; Sasaki, M.; Ischiropoulos, H.;
Przedborski, S.; Dawson, T. M.; Dawson, V. L.: DJ-1 gene deletion
reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc.
Nat. Acad. Sci. 104: 14807-14812, 2007.

4. Annesi, G.; Savettieri, G.; Pugliese, P.; D'Amelio, M.; Tarantino,
P.; Ragonese, P.; La Bella, V.; Piccoli, T.; Civitelli, D.; Annesi,
F.; Fierro, B.; Piccoli, F.; Arabia, G.; Caracciolo, M.; Canadiano,
I. C. C.; Quattrone, A.: DJ-1 mutations and parkinsonism-dementia-amyotrophic
lateral sclerosis complex. Ann. Neurol. 58: 803-807, 2005.

5. Bjorkblom, B.; Adilbayeva, A.; Maple-Grodem, J.; Piston, D.; Okvist,
M.; Xu, X. M.; Brede, C.; Larsen, J. P.; Moller, S. G.: Parkinson
disease protein DJ-1 binds metals and protects against metal-induced
cytotoxicity. J. Biol. Chem. 288: 22809-22820, 2013.

6. Bonifati, V.; Rizzu, P.; van Baren, M. J.; Schaap, O.; Breedveld,
G. J.; Krieger, E.; Dekker, M. C. J.; Squitieri, F.; Ibanez, P.; Joosse,
M.; van Dongen, J. W.; Vanacore, N.; van Swieten, J. C.; Brice, A.;
Meco, G.; van Duijn, C. M.; Oostra, B. A.; Heutink, P.: Mutations
in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:
256-259, 2003.

7. Chen, J.; Li, L.; Chin, L.-S.: Parkinson disease protein DJ-1
converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum.
Molec. Genet. 19: 2395-2408, 2010.

8. Clements, C. M.; McNally, R. S.; Conti, B. J.; Mak, T. W.; Ting,
J. P.-Y.: DJ-1, a cancer- and Parkinson's disease-associated protein,
stabilizes the antioxidant transcriptional master regulator Nrf2. Proc.
Nat. Acad. Sci. 103: 15091-15096, 2006.

9. Cookson, M. R.: Crystallizing ideas about Parkinson's disease. Proc.
Nat. Acad. Sci. 100: 9111-9113, 2003.

10. Guzman, J. N.; Sanchez-Padilla, J.; Wokosin, D.; Kondapalli, J.;
Ilijic, E.; Schumacker, P. T.; Surmeier, D. J.: Oxidant stress evoked
by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468:
696-700, 2010.

11. Hering, R.; Strauss, K. M.; Tao, X.; Bauer, A.; Woitalla, D.;
Mietz, E.-M.; Petrovic, S.; Bauer, P.; Schaible, W.; Muller, T.; Schols,
L.; Klein, C.; Berg, D.; Meyer, P. T.; Schulz, J. B.; Wollnik, B.;
Tong, L.; Kruger, R.; Riess, O.: Novel homozygous p.E64D mutation
in DJ1 in early onset Parkinson disease (PARK7). Hum. Mutat. 24:
321-329, 2004.

12. Irrcher, I.; Aleyasin, H.; Seifert, E. L.; Hewitt, S. J.; Chhabra,
S.; Phillips, M.; Lutz, A. K.; Rousseaux, M. W. C.; Bevilacqua, L.;
Jahani-Asl, A.; Callaghan, S.; MacLaurin, J. G.; and 11 others:
Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial
dynamics. Hum. Molec. Genet. 19: 3734-3746, 2010.

13. Junn, E.; Taniguchi, H.; Jeong, B. S.; Zhao, X.; Ichijo, H.; Mouradian,
M. M.: Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating
kinase 1 activity and cell death. Proc. Nat. Acad. Sci. 102: 9691-9696,
2005.

14. Kim, R. H.; Smith, P. D.; Aleyasin, H.; Hayley, S.; Mount, M.
P.; Pownall, S.; Wakeham, A.; You-Ten, A. J.; Kalia, S. K.; Horne,
P.; Westaway, D.; Lozano, A. M.; Anisman, H.; Park, D. S.; Mak, T.
W.: Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) and oxidative stress. Proc. Nat. Acad. Sci. 102: 5215-5220,
2005.

15. Macedo, M. G.; Anar, B.; Bronner, I. F.; Cannella, M.; Squitieri,
F.; Bonifati, V.; Hoogeveen, A.; Heutink, P.; Rizzu, P.: The DJ-1(L166P)
mutant protein associated with early onset Parkinson's disease is
unstable and forms higher-order protein complexes. Hum. Molec. Genet. 12:
2807-2816, 2003.

16. Meulener, M. C.; Xu, K.; Thomson, L.; Ischiropoulos, H.; Bonini,
N. M.: Mutational analysis of DJ-1 in Drosophila implicates functional
inactivation by oxidative damage and aging. Proc. Nat. Acad. Sci. 103:
12517-12522, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 14978,
2006.

17. Moore, D. J.; Zhang, L.; Troncoso, J.; Lee, M. K.; Hattori, N.;
Mizuno, Y.; Dawson, T. M.; Dawson, V. L.: Association of DJ-1 and
parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum.
Molec. Genet. 14: 71-84, 2005.

18. Nagakubo, D.; Taira, T.; Kitaura, H.; Ikeda, M.; Tamai, K.; Iguchi-Ariga,
S. M. M.; Ariga, H.: DJ-1, a novel oncogene which transforms mouse
NIH3T3 cells in cooperation with ras. Biochem. Biophys. Res. Commun. 231:
509-513, 1997.

19. Ottolini, D.; Cali, T.; Negro, A.; Brini, M.: The Parkinson disease-related
protein DJ-1 counteracts mitochondrial impairment induced by the tumour
suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria
tethering. Hum. Molec. Genet. 22: 2152-2168, 2013.

20. Rizzu, P.; Hinkle, D. A.; Zhukareva, V.; Bonifati, V.; Severijnen,
L.-A.; Martinez, D.; Ravid, R.; Kamphorst, W.; Eberwine, J. H.; Lee,
V. M.-Y.; Trojanowski, J. Q.; Heutink, P.: DJ-1 colocalizes with
tau inclusions: a link between parkinsonism and dementia. Ann. Neurol. 55:
113-118, 2004.

21. Takahashi, K.; Taira, T.; Niki, T.; Seino, C.; Iguchi-Ariga, S.
M. M.; Ariga, H.: DJ-1 positively regulates the androgen receptor
by impairing the binding of PIASx-alpha to the receptor. J. Biol.
Chem. 276: 37556-37563, 2001.

22. Takahashi-Niki, K.; Niki, T.; Taira, T.; Iguchi-Ariga, S. M. M.;
Ariga, H.: Reduced anti-oxidative stress activities of DJ-1 mutants
found in Parkinson's disease patients. Biochem. Biophys. Res. Commun. 320:
389-397, 2004.

23. Tang, B.; Xiong, H.; Sun, P.; Zhang, Y.; Wang, D.; Hu, Z.; Zhu,
Z.; Ma, H.; Pan, Q.; Xia, J.; Xia, K.; Zhang, Z.: Association of
PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's
disease. Hum. Molec. Genet. 15: 1816-1825, 2006.

24. Wagenfeld, A.; Gromoll, J.; Cooper, T. G.: Molecular cloning
and expression of rat contraception associated protein 1 (CAP1), a
protein putatively involved in fertilization. Biochem. Biophys. Res.
Commun. 251: 545-549, 1998.

25. Wilson, M. A.; Collins, J. L.; Hod, Y.; Ringe, D.; Petsko, G.
A.: The 1.1-Angstrom resolution crystal structure of DJ-1, the protein
mutated in autosomal recessive early onset Parkinson's disease. Proc.
Nat. Acad. Sci. 100: 9256-9261, 2003.

26. Xiong, H.; Wang, D.; Chen, L.; Choo, Y. S.; Ma, H.; Tang, C.;
Xia, K.; Jiang, W.; Ronai, Z.; Zhuang, X.; Zhang, Z.: Parkin, PINK1,
and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein
degradation. J. Clin. Invest. 119: 650-660, 2009.

27. Xu, J.; Zhong, N.; Wang, H.; Elias, J. E.; Kim, C. Y.; Woldman,
I.; Pifl, C.; Gygi, S. P.; Geula, C.; Yankner, B. A.: The Parkinson's
disease-associated DJ-1 protein is a transcriptional co-activator
that protects against neuronal apoptosis. Hum. Molec. Genet. 14:
1231-1241, 2005.

28. Zhang, L.; Shimoji, M.; Thomas, B.; Moore, D. J.; Yu, S.-W.; Marupudi,
N. I.; Torp, R.; Torgner, I. A.; Ottersen, O. P.; Dawson, T. M.; Dawson,
V. L.: Mitochondrial localization of the Parkinson's disease related
protein DJ-1: implications for pathogenesis. Hum. Molec. Genet. 14:
2063-2073, 2005.

*FIELD* CN
Patricia A. Hartz - updated: 1/7/2014
Patricia A. Hartz - updated: 10/10/2013
George E. Tiller - updated: 8/5/2013
Cassandra L. Kniffin - updated: 5/15/2013
Patricia A. Hartz - updated: 8/3/2012
Ada Hamosh - updated: 1/25/2011
Cassandra L. Kniffin - updated: 10/15/2009
George E. Tiller - updated: 11/18/2008
George E. Tiller - updated: 5/19/2008
Cassandra L. Kniffin - updated: 3/3/2008
Cassandra L. Kniffin - updated: 1/17/2008
George E. Tiller - updated: 10/31/2007
Patricia A. Hartz - updated: 12/1/2006
Paul J. Converse - updated: 11/9/2006
Cassandra L. Kniffin - updated: 3/6/2006
George E. Tiller - updated: 1/31/2006
Cassandra L. Kniffin - updated: 10/17/2005
Patricia A. Hartz - updated: 8/15/2005
Cassandra L. Kniffin - updated: 4/13/2005
Victor A. McKusick - updated: 12/9/2004
Cassandra L. Kniffin - updated: 6/7/2004
Cassandra L. Kniffin - updated: 12/30/2003
Victor A. McKusick - updated: 9/8/2003
Cassandra L. Kniffin - updated: 1/15/2003

*FIELD* CD
Jennifer P. Macke: 4/20/1998

*FIELD* ED
mgross: 01/09/2014
mcolton: 1/7/2014
mgross: 10/10/2013
alopez: 8/5/2013
carol: 5/20/2013
ckniffin: 5/15/2013
carol: 10/8/2012
joanna: 10/4/2012
mgross: 8/8/2012
terry: 8/8/2012
terry: 8/3/2012
alopez: 1/31/2011
terry: 1/25/2011
carol: 7/12/2010
carol: 2/24/2010
wwang: 10/27/2009
ckniffin: 10/15/2009
ckniffin: 1/9/2009
wwang: 11/18/2008
wwang: 5/23/2008
terry: 5/19/2008
wwang: 3/19/2008
ckniffin: 3/3/2008
wwang: 3/3/2008
ckniffin: 1/17/2008
alopez: 11/5/2007
terry: 10/31/2007
wwang: 12/1/2006
mgross: 11/14/2006
terry: 11/9/2006
wwang: 3/10/2006
ckniffin: 3/6/2006
wwang: 2/7/2006
terry: 1/31/2006
wwang: 10/25/2005
ckniffin: 10/17/2005
wwang: 10/4/2005
ckniffin: 9/20/2005
mgross: 8/15/2005
wwang: 4/28/2005
wwang: 4/25/2005
ckniffin: 4/13/2005
tkritzer: 1/5/2005
terry: 12/9/2004
carol: 6/10/2004
ckniffin: 6/8/2004
ckniffin: 6/7/2004
tkritzer: 1/16/2004
ckniffin: 12/30/2003
cwells: 9/10/2003
terry: 9/8/2003
carol: 1/16/2003
ckniffin: 1/15/2003
dholmes: 5/12/1998

MIM 606324
*RECORD*
*FIELD* NO
606324
*FIELD* TI
#606324 PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK7
*FIELD* TX
A number sign (#) is used with this entry because this form of autosomal
read morerecessive early-onset Parkinson disease is caused by homozygous or
compound heterozygous mutation in the DJ1 gene (602533) on chromosome
1p36.

Other forms of early-onset Parkinson disease include PARK2 (600116),
caused by mutation in the parkin gene (602544), and PARK6 (605909),
caused by mutation in the PINK1 gene (608309).

A digenic form of Parkinson disease (see 605909) resulting from a
mutation in the DJ1 gene and a mutation in the PINK1 gene has been
reported.

For general phenotypic information and a discussion of genetic
heterogeneity of Parkinson disease, see 168600.

CLINICAL FEATURES

Van Duijn et al. (2001) reported a consanguineous family from a
genetically isolated community in the southwestern region of the
Netherlands in which 4 individuals had a form of early-onset Parkinson
disease. Onset of symptoms was before the age of 40 years with resting
tremor, postural tremor, bradykinesia, loss of postural reflexes, and an
asymmetric onset of symptoms. Three of the 4 patients also showed
psychiatric symptoms, including psychotic episodes. In all patients, the
progression of disease was slow, and there were no atypical features or
signs of involvement of additional neurologic systems.

Abou-Sleiman et al. (2003) reported 2 unrelated patients with
early-onset Parkinson disease. They presented at ages 36 and 39 years
with rigidity, bradykinesia, and tremor, with a good response to L-dopa
therapy. Both patients had psychologic disturbances early in the
disease, particularly an anxiety disorder.

- Clinical Variability

Annesi et al. (2005) reported 3 affected sibs from a consanguineous
southern Italian family in which 3 sibs had early-onset parkinsonism at
ages 36, 35, and 24 years, respectively. One sib also had features of
amyotrophic lateral sclerosis with upper and lower limb weakness,
fasciculations, and EMG evidence of denervation. He later developed
severe, bulbar involvement, muscle atrophy, and hyperreflexia with
extensor plantar responses, as well as marked cognitive impairment and
parkinsonism. He died from respiratory failure at age 43 years. The
other 2 sibs had prominent parkinsonism, hyperreflexia, urinary
incontinence, and behavioral abnormalities, such as aggression and
bulimia. Annesi et al. (2005) noted that the phenotype was reminiscent
of that reported in Guam (105500).

MAPPING

In a family with early-onset parkinsonism from a genetically isolated
community in the Netherlands, van Duijn et al. (2001) found linkage to
chromosome 1p36. Using a multiple marker spanning a disease haplotype of
16 cM, they found a multipoint linkage lod score of 4.3. On the basis of
several recombination events, the region defining the disease haplotype
was clearly separated, by 25 cM or more, from the more centromeric PARK6
locus. Therefore, the authors concluded that this was a distinct form of
the disease from PARK6.

Among 4 families with autosomal recessive early-onset parkinsonism
analyzed, Bonifati et al. (2002) found that 2 supported linkage to
PARK7, 1 with conclusive evidence.

MOLECULAR GENETICS

In the family reported by van Duijn et al. (2001) and in 1 of the
families reported by Bonifati et al. (2002), Bonifati et al. (2003)
identified mutations in the DJ1 gene that cosegregated with the disease
(602533.0001-602533.0002).

Among 185 unrelated patients with early-onset Parkinson disease,
Abou-Sleiman et al. (2003) identified 2 patients with mutations in the
DJ1 gene (602533.0003-602533.0004). The authors estimated that the
frequency of DJ1 mutations in early-onset Parkinson disease is very low,
at approximately 1%.

Among 118 familial patients and 7 sporadic patients with early-onset
Parkinson disease (range of age at onset, 12 to 78 years), Ibanez et al.
(2003) did not identify any mutations in the DJ1 gene, suggesting that
PARK7 is not a common locus for early-onset autosomal recessive
Parkinson disease. The patients came from Europe, South America,
Lebanon, Asia, Turkey, and North Africa.

In 3 affected sibs from a consanguineous southern Italian family with
early-onset parkinsonism, amyotrophic lateral sclerosis, and cognitive
impairment, Annesi et al. (2005) identified double homozygosity for 2
mutations in the DJ1 gene (602533.0006).

Alcalay et al. (2010) identified a mutation in the DJ1 gene in 1 (0.2%)
of 953 patients with early-onset PD before age 51, including 77 and 139
individuals of Hispanic and Jewish ancestry, respectively.

ANIMAL MODEL

Ramsey et al. (2010) noted that several in vitro studies had suggested
that DJ1 could inhibit the formation and protect against the deleterious
effects of SNCA (163890) aggregation. They crossbred transgenic mice
(M83) expressing the human pathogenic SNCA A53T mutation (163890.0001),
which causes PARK1 (168601), on a DJ1-null background (M83-DJ-null mice)
to determine the effects of the lack of DJ1 in these mice. M83 and
M83-DJ-null mice displayed a similar onset of disease and pathologic
changes, and none of the analyses to assess for changes in pathogenesis
revealed any significant differences between M83 and M83-DJ-null mice.
The authors suggested that DJ1 may not function to modulate SNCA
directly and does not appear to play a role in protecting against the
deleterious effects of A53T in vivo. Ramsey et al. (2010) speculated
that SNCA and DJ1 mutations may lead to Parkinson disease via
independent mechanisms.

*FIELD* RF
1. Abou-Sleiman, P. M.; Healy, D. G.; Quinn, N.; Lees, A. J.; Wood,
N. W.: The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann.
Neurol. 54: 283-286, 2003.

2. Alcalay, R. N.; Caccappolo, E.; Mejia-Santana, H.; Tang, M. X.;
Rosado, L.; Ross, B. M.; Verbitsky, M.; Kisselev, S.; Louis, E. D.;
Comella, C.; Colcher, A.; Jennings, D.; and 21 others: Frequency
of known mutations in early-onset Parkinson disease: implication for
genetic counseling: the Consortium on Risk for Early Onset Parkinson
Disease study. Arch. Neurol. 67: 1116-1122, 2010.

3. Annesi, G.; Savettieri, G.; Pugliese, P.; D'Amelio, M.; Tarantino,
P.; Ragonese, P.; La Bella, V.; Piccoli, T.; Civitelli, D.; Annesi,
F.; Fierro, B.; Piccoli, F.; Arabia, G.; Caracciolo, M.; Canadiano,
I. C. C.; Quattrone, A.: DJ-1 mutations and parkinsonism-dementia-amyotrophic
lateral sclerosis complex. Ann. Neurol. 58: 803-807, 2005.

4. Bonifati, V.; Breedveld, G. J.; Squitieri, F.; Vanacore, N.; Brustenghi,
P.; Harhangi, B. S.; Montagna, P.; Cannella, M.; Fabbrini, G.; Rizzu,
P.; van Duijn, C. M.; Oostra, B. A.; Meco, G.; Heutink, P.: Localization
of autosomal recessive early-onset parkinsonism to chromosome 1p36
(PARK7) in an independent dataset. Ann. Neurol. 51: 253-256, 2002.

5. Bonifati, V.; Rizzu, P.; van Baren, M. J.; Schaap, O.; Breedveld,
G. J.; Krieger, E.; Dekker, M. C. J.; Squitieri, F.; Ibanez, P.; Joosse,
M.; van Dongen, J. W.; Vanacore, N.; van Swieten, J. C.; Brice, A.;
Meco, G.; van Duijn, C. M.; Oostra, B. A.; Heutink, P.: Mutations
in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:
256-259, 2003.

6. Ibanez, P.; De Michele, G.; Bonifati, V.; Lohmann, E.; Thobois,
S.; Pollak, P.; Agid, Y.; Heutink, P.; Durr, A.; Brice, A.; French
Parkinson's Disease Genetics Study Group: Screening for DJ-1 mutations
in early onset autosomal recessive parkinsonism. Neurology 61: 1429-1431,
2003.

7. Ramsey, C. P.; Tsika, E.; Ischiropoulos, H.; Giasson, B. I.: DJ-1
deficient mice demonstrate similar vulnerability to pathogenic ala53-to-thr
human alpha-syn toxicity. Hum. Molec. Genet. 19: 1425-1437, 2010.

8. van Duijn, C. M.; Dekker, M. C. J.; Bonifati, V.; Galjaard, R.
J.; Houwing-Duistermaat, J. J.; Snijders, P. J. L. M.; Testers, L.;
Breedveld, G. J.; Horstink, M.; Sandkuijl, L. A.; van Swieten, J.
C.; Oostra, B. A.; Heutink, P.: PARK7, a novel locus for autosomal
recessive early-onset parkinsonism, on chromosome 1p36. Am. J. Hum.
Genet. 69: 629-634, 2001.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Blepharospasm may occur

NEUROLOGIC:
[Central nervous system];
Resting tremor;
Postural tremor;
Bradykinesia;
Muscular rigidity;
[Behavioral/psychiatric manifestations];
Anxiety disorders;
Psychotic episodes;
'Neurotic' signs and symptoms

MISCELLANEOUS:
Onset before age 40 years;
Slow progression;
Good response to L-dopa initially

MOLECULAR BASIS:
Caused by mutation in the DJ1 gene (602533.0001)

*FIELD* CD
Cassandra L. Kniffin: 12/30/2003

*FIELD* ED
ckniffin: 12/30/2003

*FIELD* CN
George E. Tiller - updated: 11/17/2011
Cassandra L. Kniffin - updated: 6/23/2011
Cassandra L. Kniffin - updated: 2/4/2004
Cassandra L. Kniffin - updated: 1/15/2003
Victor A. McKusick - updated: 4/16/2002

*FIELD* CD
Victor A. McKusick: 9/28/2001

*FIELD* ED
carol: 04/24/2012
terry: 3/26/2012
carol: 11/22/2011
terry: 11/17/2011
wwang: 6/29/2011
ckniffin: 6/23/2011
wwang: 10/27/2009
alopez: 8/31/2009
terry: 8/25/2009
ckniffin: 1/9/2009
alopez: 10/30/2006
wwang: 10/4/2005
tkritzer: 2/24/2004
ckniffin: 2/4/2004
tkritzer: 1/16/2004
ckniffin: 12/30/2003
carol: 1/16/2003
ckniffin: 1/15/2003
cwells: 5/1/2002
cwells: 4/29/2002
terry: 4/16/2002
alopez: 9/28/2001