Association of transcription factor polymorphisms PITX3 and EN1 with Parkinson's disease
Introduction
Degeneration of midbrain dopaminergic neurons (mDA) is considered the pathological hallmark of Parkinson's disease (PD). At the time of onset of motor symptoms in PD, 50% of dopaminergic neurons in the substantia nigra, pars compacta (SNpc) have already been lost (Fearnley and Lees, 1991). Pathological studies and positron emission tomography studies with 18F-Dopa suggest that the duration of the preclinical period in PD is around 5 years (Fearnley and Lees, 1991, Morrish et al., 1998).
Recently, genetic variants in the genes coding for transcription factors PITX3 and Engrailed 1 (EN1) have been suggested as risk factors for PD (Bergman et al., 2008, Fuchs et al., 2007). PITX3 and EN1 are members of the homeodomain protein family, which play an integral role in the development and survival of mDA neurons: Nurr1, also a homeodomain transcription factor relevant for development and maintenance of dopaminergic neurons, has been associated with familial PD and its gene expression is significantly lower in patients with PD compared to healthy controls (Le et al., 2008, Le et al., 2003). However, these findings could not be replicated by others (Zimprich et al., 2003). A deletion in the promoter region of PITX3 has been shown to underlie the pathology in the aphakia mouse model, which is also characterized by a loss of mDA neurons (Semina et al., 2000, Smidt et al., 2004). PTIX3 gene expression in the brain is highly restricted to mDA neurons and plays a crucial role in the development of dopaminergic neurons in the substantia nigra (Nunes et al., 2003, Smidt et al., 1997). The specificity of degeneration of dopaminergic neurons expressing aldehyde-dehydrogenase 2 (ALDH2) projecting from the SNpc to the dorsal striatum is highlighted by the PITX3-mediated facilitation of differentiation of mouse embryonic stem cells into this particular subtype of DA-neurons, which are most vulnerable in PD (Chung et al., 2005).
PTIX3-deficient mice furthermore exhibit locomotor deficits that are reversible after the administration of L-DOPA (Hwang et al., 2005). Impaired motor skills and anhedonic behavior have been described in mutant mice with only one functioning EN1 allele (EN1+/−) in an EN2 wild-type environment, as well as a significant loss of ventral mDA neurons, which occurred progressively between week 8 and 24 after birth, suggesting a function as survival factor (Sonnier et al., 2007). Recently, microRNA miR-133b was identified as a regulating factor in mDA maturation and functions in a negative feedback circuit involving the transcription factor PITX3, which induces transcription of miR-133b (Kim et al., 2007).
The loss of Engrailed genes leads to apoptosis of mDA neurons mediated by activated caspase 3, a pathway suggested to be relevant in the pathogenesis of PD (Alberi et al., 2004, Hartmann et al., 2000).
Therefore, transcription factors for mDA neurons have been considered potential candidate genes in PD. In a hypothesis-driven candidate gene approach, Fuchs and coworkers genotyped 54 single nucleotide polymorphisms (SNP) in genes coding for the transcription factors EN1, Engrailed 2 (EN2), PITX3, LMX1B, and OTX2, and found a highly significant association in PD patients for the rs3758549 C > T polymorphism, located in the putative promoter region of PITX3. Also, the rs4144782 A > G polymorphism in the intronic region of EN1 showed a significant association with PD (Fuchs et al., 2007). The potential functional relevance of the variants in the genetic PITX3 region in the PD pathogenesis was underlined by a subsequent study on a Swedish sample showing a significant association of early-onset PD and the A-allele of the rs4919621 PITX3 polymorphism, in contrast to late-onset PD and controls. However, when all PD samples were compared to controls, no significant association remained for rs4919621. Also, the findings on rs3758349 could not be replicated (Bergman et al., 2008).
The aim of this study was to investigate a potential association of PITX3 and EN1 polymorphisms in a multi-SNP approach in an independent sample of PD patients and controls from Austria.
Section snippets
Patients and controls
After obtaining informed consent, 365 PD patients (249 males, 116 females) were recruited at the movement disorders clinic at the Department of Neurology, Medical University, as well as in affiliated clinics in Vienna on a consecutive basis. The clinical diagnosis of idiopathic PD was made by a movement disorders specialist, based on standard clinical criteria (UK Brain Bank criteria (Hughes et al., 1992)). After documentation of the clinical phenotype, 9 ml venous blood was collected
Results
With the exception of rs3758549, all SNPs were in Hardy–Weinberg equilibrium, both in the patient and in the control group. Due to a different distribution of sex in patients and controls (sex effect: p = 0.001), all model calculations were corrected for sex by including sex and genotype–sex interaction as cofactors in all logistic regressions (Table 1).
The PITX3 promoter SNP rs3758549 showed a strong correlation in the genotype association test in the total sample of patients (p = 0.0002) as well
Discussion
The analysis of transcription factor polymorphisms in PD represent a hypothesis-driven candidate gene approach in the quest of potential genetic risk factors for this disease. Large sample sets are often needed to show sufficiently powered effects of polymorphisms that are common in the general population. Therefore, the association between PITX3 and EN1 polymorphisms and PD as recently described in a German patient sample could demonstrate a previously unrecognized genetic risk predisposition
Conflicts of interest statement
There are no conflicts of interests in any of the authors.
Acknowledgements
We thank Sonja Scholz, MD (Molecular Genetics Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA) for assistance in interpreting the genotype data of the NINDS-Genome-Wide Genotyping in Parkinson's Disease dataset.
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