Systematic genetic analysis of thePITX3gene in patients with Parkinson disease

Guo, Yi; Le, Wei Dong; Jankovic, Joseph; Yang, Hua Rong; Xu, Hong; Xie, Wen; Song, Zhi; Deng, Hao

doi:10.1002/mds.23693

Cited by 22 publications

(28 citation statements)

References 17 publications

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“…The search using PubMed, MEDLINE, EMBASE, Science Citation Index EXPANDED, NICE, CENTRAL and PDGene databases showed 15 case-control studies on SNPs in the PITX3 gene [9,10,11,12,13,14,15,16,17,18,19,25,26,27,28]. However, one of them reported preliminary data [19] and these data were included in a further publication by the same group [14].…”

Section: Resultsmentioning

confidence: 99%

“…Finally, we also performed a subgroup analysis on the risk for Caucasian and Chinese populations, and for early-onset PD and late-onset PD in those reports where these data were available [11,13,14,16,17]. …”

Section: Methodsmentioning

confidence: 99%

“…Yu et al [11] found an increased risk for PD and for early-onset PD related with the minor allele, and Liu et al [12] reported an increased risk for late-onset PD. Other authors did not find an association of these SNPs with the risk of developing PD [13,14,15], late-onset PD [11,13,14,16,17] and early-onset PD [13,14,16]. …”

Section: Introductionmentioning

confidence: 99%

“…Guo et al [14] reported an association of these SNPs with the risk of developing PD, and two studies described an association of these SNPs with early-onset PD [13,14]. Two studies described an association with early-onset PD [13,14].…”

Section: Introductionmentioning

confidence: 99%

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PITX3 and Risk for Parkinson's Disease: A Systematic Review and Meta-Analysis

et al. 2013

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Background/Aims: Several single nucleotide polymorphisms (SNPs) in the PITX3 gene have been associated with the risk for Parkinson's disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on the risk of PD related with these polymorphisms. Methods: The systematic review was done using several databases. Eligible studies were included in the meta-analysis that was carried out using Meta-DiSc 1.1.1 software. Heterogeneity between studies was tested using the Q-statistic. Results: The meta-analysis included eight association studies for the PITX3 rs3758549 SNP (4,052 PD patients, 3,949 controls), eight studies for the PITX3 rs2281983 SNP (4,309 PD patients, 4,287 controls), and six studies for the rs4919621 SNP (2,724 PD patients, 2,285 controls), and the risk for PD, global diagnostic odds ratios (95% confidence intervals) for rs3758549, rs2281983, and rs4919621 were, respectively, 1.00 (0.89-1.12) (p = 0.979), 0.99 (0.91-1.09) (p = 0.896), and 0.98 (0.83-1.16) (p = 0.844) for the total group. The separate analysis in Caucasian and Chinese subjects on the frequency of the minor allele of the three SNPs analyzed did not show significant differences between PD patients and controls in both subgroups. rs2281983 and rs4919621 SNPs were related with early-onset PD risk in Caucasians. Conclusion: The results of the meta-analysis suggest that rs3758549, rs2281983, and rs4919621 SNPs are not major determinants of the risk for PD.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PITX3 and Risk for Parkinson's Disease: A Systematic Review and Meta-Analysis

et al. 2013

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“…Most important of these are: Small eye (gene symbol: Sey; Roberts, 1967), later in PITX3 are responsible for varying degree of ocular phenotypes including cataract, anterior segment mesenchymal dysgenesis and microphthalmia (Berry et al, 2004, Bidinost et al, 2006, Burdon et al, 2006, Semina et al, 1998, and various polymorphisms have been linked to Parkinson's disease (Bergman et al, 2010, Fuchs et al, 2009, Gui et al, 2012, Guo et al, 2011, Haubenberger et al, 2011, Liu et al, 2011.…”

Section: Introductionmentioning

confidence: 99%

Pitx3 directly regulates Foxe3 during early lens development

Ahmad¹,

Aslam²,

Muenster³

et al. 2013

Int. J. Dev. Biol.

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Pitx3 is a bicoid-related homeodomain transcription factor critical for the development of the ocular lens, mesencephalic dopaminergic neurons and skeletal muscle. In humans, mutations in PITX3 are responsible for cataracts and anterior segment abnormalities of varying degree; polymorphisms are associated with Parkinson's disease. In aphakia (ak) mice, two deletions in the promoter region of Pitx3 cause abnormal lens development. Here, we investigated systematically the role of Pitx3 in lens development including its molecular targets responsible for the ak phenotype. We have shown that ak lenses exhibit reduced proliferation and aberrant fiber cell differentiation. This was associated with loss of Foxe3 expression, complete absence of Prox1 expression, reduced expression of e-tubulin and earlier expression of g-crystallin during lens development. Using EMSA and ChIP assays, we demonstrated that Pitx3 binds to an evolutionary conserved bicoid-binding site on the 5'-upstream region of Foxe3. Finally, Pitx3 binding to 5'-upstream region of Foxe3 increased transcriptional activity significantly in a cell-based reporter assay. Identification of Foxe3 as a transcriptional target of Pitx3 explains at least in part some of the phenotypic similarities of the ak and dyl mice (dysgenic lens, a Foxe3 allele). These findings enhance our understanding of the molecular cascades which subserve lens development.

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Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L‐DOPA in the cerebrospinal fluid

Derwińska¹,

Mierzewska²,

Goszczańska³

et al. 2012

American J of Med Genetics Pt B

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The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3(-/-) mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ∼317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep.

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Systematic genetic analysis of thePITX3gene in patients with Parkinson disease

Cited by 22 publications

References 17 publications

<b><i>PITX3</i></b> and Risk for Parkinson's Disease: A Systematic Review and Meta-Analysis

<b><i>PITX3</i></b> and Risk for Parkinson's Disease: A Systematic Review and Meta-Analysis

Pitx3 directly regulates Foxe3 during early lens development

Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L‐DOPA in the cerebrospinal fluid

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