The transcription factor PITX3 is associated with sporadic Parkinson's disease.
Parkinson's disease (PD) is a progressive neurodegenerative disease with typical motor symptoms due to the preferential loss of midbrain dopaminergic (mDA) neurons in the Substantia nigra pars compacta. Several proteins of the homeodomain family are crucial for the development of mDA neurons. These proteins remain expressed into adulthood with largely unknown functions, but potentially influence mDA neuronal survival. To determine whether genetic variation in these genes plays a role in sporadic PD, we performed a genetic association study in a screening sample of 340 PD patients and 680 controls and a large replication sample of 669 PD patients and 669 controls using 54 single nucleotide polymorphisms in and around the Engrailed 1/2, PITX3, LMX1B and OTX2 genes. We provide evidence for a novel, strong and reproducible association of the PITX3 promoter SNP rs3758549: C>T (p=0.004) with PD. The C-allele appears to be a recessive risk allele with an estimated population frequency of 83%. An allele-dependent dysregulation of PITX3 expression might contribute to the susceptibility to PD.
Fuchs
Julia
J
Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Otfried-Müller-Strasse 27, 72076 Tübingen, Germany. jfuchs@biologie.ens.fr
Mueller
Jakob C
JC
Lichtner
Peter
P
Schulte
Claudia
C
Munz
Marita
M
Berg
Daniela
D
Wüllner
Ullrich
U
Illig
Thomas
T
Sharma
Manu
M
Gasser
Thomas
T
D001923:Brain Chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013378:Substantia Nigra / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*
D005819:Genetic Markers; D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3