Genetics of Parkinson disease.
Parkinson disease (PD) is the second most common neurodegenerative disorder. Recent studies have consistently demonstrated that in some families, disease is attributable to a mutation in a single gene. To date, genetic analyses have detected linkage to six chromosomal regions and have identified three causative genes: PARK1 (alpha-synuclein), PARK2 (parkin), and PARK7 (DJ-1). In addition, mutations in several other genes have been implicated in familial PD. Identification of the mutations in these genes has led to the recognition that the ubiquitin-proteasome system is an important pathway that may be disrupted in PD. Studies are ongoing to identify additional genes that may contribute to PD susceptibility, particularly in late-onset families without a clear pattern of disease inheritance. With the identification of mutations in particular genes and the likely role of additional genes that are important in PD risk-susceptibility, appropriate protocols must be developed so that accurate and informative genetic counseling can be offered to families in which one or more members has PD. Further diagnostic testing should be delayed until more is learned about the frequency, penetrance, and risk assessment of certain gene mutations. Important lessons can be learned from the implementation of counseling protocols for other neurodegenerative disorders, such as Huntington disease and Alzheimer disease.
Pankratz
Nathan
N
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-525, USA. nathan@pankratz.com
Foroud
Tatiana
T
D005817:Genetic Counseling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein
D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1
Cell. 2001 Jun 29;105(7):891-902
11439185
Science. 2001 Jul 13;293(5528):263-9
11431533
Am J Hum Genet. 2001 Sep;69(3):629-34
11462174
Ann Neurol. 2001 Sep;50(3):293-300
11558785
Neurology. 2004 May 11;62(9):1616-8
15136695
Neurology. 1973 Mar;23(3):239-44
4735177
Brain. 1973 Sep;96(3):495-506
4147573
Adv Neurol. 1984;40:333-9
6695609
Can J Neurol Sci. 1986 Aug;13(3):248-51
3742341
Brain Pathol. 1992 Oct;2(4):309-20
1341965
Neurology. 1996 Jul;47(1):160-6
8710071
Am J Hum Genet. 1996 Nov;59(5):983-9
8900224
Biochem Biophys Res Commun. 1997 Feb 13;231(2):509-13
9070310
Science. 1997 Jun 27;276(5321):2045-7
9197268
Free Radic Res. 2001 Dec;35(6):885-93
11811539
Am J Hum Genet. 2002 Apr;70(4):985-93
11875758
Ann Neurol. 2002 Mar;51(3):296-301
11891824
Neurology. 2002 Mar 26;58(6):881-4
11914402
Am J Hum Genet. 2002 May;70(5):1089-95
11920285
Neurology. 2002 Apr 23;58(8):1239-46
11971093
Nat Med. 2002 Jun;8(6):600-6
12042811
Am J Hum Genet. 2002 Jul;71(1):124-35
12058349
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8968-73
12084935
Ann Neurol. 2002 May;51(5):621-5
12112109
Am J Med Genet. 2002 Jul 8;114(5):584-91
12116199
J Med Genet. 2002 Jul;39(7):489-92
12114481
Biol Pharm Bull. 2002 Jul;25(7):853-6
12132656
Neurology. 2002 Oct 8;59(7):1118; author reply 1118
12370484
Ann Neurol. 2002 Nov;52(5):549-55
12402251
Nat Genet. 2003 Jan;33(1):85-9
12496759
Science. 2003 Jan 10;299(5604):256-9
12446870
Neurology. 2003 Mar 11;60(5):796-801
12629236
Am J Hum Genet. 2003 Apr;72(4):804-11
12618962
Am J Hum Genet. 2003 Apr;72(4):1053-7
12638082
Ann Neurol. 2003 May;53(5):624-9
12730996
Arch Neurol. 2003 May;60(5):722-5
12756136
Hum Mol Genet. 2003 Jun 1;12(11):1223-31
12761037
Mov Disord. 2003 Jul;18(7):758-63
12815654
Ann N Y Acad Sci. 2003 Jun;991:93-100
12846977
Med J Aust. 2003 Aug 4;179(3):167-9
12885289
J Biol Chem. 2003 Sep 19;278(38):36588-95
12851414
Hum Mol Genet. 2003 Oct 15;12(20):2599-608
12925570
Science. 2003 Oct 31;302(5646):841
14593171
FASEB J. 2003 Nov;17(14):2151-3
12958153
Neurology. 1999 Oct 22;53(7):1415-21
10534244
Neuron. 1999 Dec;24(4):879-92
10624951
Nature. 2000 Mar 23;404(6776):394-8
10746727
N Engl J Med. 2000 May 25;342(21):1560-7
10824074
Nat Genet. 2000 Jul;25(3):302-5
10888878
Nat Genet. 1998 Feb;18(2):106-8
9462735
Nat Genet. 1998 Mar;18(3):262-5
9500549
Ann Neurol. 1998 Mar;43(3):394-7
9506559
Hum Mol Genet. 1998 Apr;7(4):751-3
9499430
Nature. 1998 Apr 9;392(6676):605-8
9560156
Neurology. 1998 Apr;50(4):1136-7
9566408
Nature. 1998 Oct 1;395(6701):451-2
9774100
Lancet. 1998 Oct 24;352(9137):1355-6
9802278
J Cell Biol. 1998 Dec 28;143(7):1883-98
9864362
JAMA. 1999 Jan 27;281(4):341-6
9929087
Hum Mol Genet. 1999 Apr;8(4):567-74
10072423
Mov Disord. 1999 Mar;14(2):219-24
10091612
Genet Test. 1999;3(1):115-9
10464585
Biochem Biophys Res Commun. 1998 Oct 20;251(2):545-9
9792810
Nat Med. 2001 Oct;7(10):1144-50
11590439
J Neurol. 2001 Oct;248(10):833-40
11697518
JAMA. 2001 Nov 14;286(18):2239-44
11710888
J Biol Chem. 2001 Nov 23;276(47):44284-96
11553618
Mov Disord. 2001 Nov;16(6):1007-13
11748731
Mov Disord. 2001 Nov;16(6):1115-9
11748744
Ann Neurol. 2002 Jan;51(1):14-8
11782979
Ann Neurol. 2000 Jul;48(1):65-71
10894217
Neuroreport. 2000 Jul 14;11(10):2079-82
10923647
Trends Biochem Sci. 2000 Nov;25(11):544-8
11084366
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13354-9
11078524
Mov Disord. 2000 Nov;15(6):1070-4
11104188
Am J Hum Genet. 2001 Apr;68(4):895-900
11254447
FASEB J. 2001 Apr;15(6):916-26
11292651
Free Radic Biol Med. 2001 May 15;30(10):1163-70
11369507