Publications by authors named "Wataru Satake"

36 Publications

TUBB3 E410K syndrome with childhood-onset non-alcoholic steatohepatitis.

J Clin Endocrinol Metab 2021 Aug 26. Epub 2021 Aug 26.

Department of Pediatrics, Kyoto Prefectural University of Medicine.

Context: Nonalcoholic fatty liver disease (NAFLD) is becoming a major issue worldwide, even in children. Multiple parallel hits hypothesis has been suggested as progress of NAFLD, but the mechanism of NAFLD is not completely understood. β-Tubulin is essential in mitoses, neuronal migration, and axon guidance during neuronal development. Pathogenic variants in the TUBB3 gene were shown to be associated with a wide spectrum of neurological abnormalities, but not accompanied with hepatic complications, such as NAFLD.

Case Description: A 11-year-old girl has been followed up as atypical Moebius syndrome since infancy, as she was born with bilateral ptosis, paralytic strabismus, and facial weakness. At the age of 7 years, she was diagnosed with TUBB3 E410K syndrome by whole exome sequencing. At the age of 10 years, her blood examination revealed elevated liver transaminase levels, which persisted for almost 2 years. She underwent liver biopsy, the results of which was suggestive of non-alcoholic steatohepatitis (NASH). The expression of TUBB3 was absent, but that of tyrosine hydroxylase (TH) was present in the parenchymal nerve fibers of the liver. On the other hand, in comparison with an autopsy case of NASH and a normal control, these showed co-expression of TUBB3 and TH in the liver.

Conclusion: We report the first case of TUBB3 E410K syndrome accompanied with NASH. This case suggests that TUBB3 mutation may be associated with the pathogenesis and progression of NASH in humans.
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http://dx.doi.org/10.1210/clinem/dgab628DOI Listing
August 2021

Trans-Ethnic Fine-Mapping of the Major Histocompatibility Complex Region Linked to Parkinson's Disease.

Mov Disord 2021 08 11;36(8):1805-1814. Epub 2021 May 11.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Despite evidence for the role of human leukocyte antigen (HLA) in the genetic predisposition to Parkinson's disease (PD), the complex haplotype structure and highly polymorphic feature of the major histocompatibility complex (MHC) region has hampered a unified insight on the genetic risk of PD. In addition, a majority of the reports focused on Europeans, lacking evidence on other populations.

Objectives: The aim of this study is to elucidate the genetic features of the MHC region associated with PD risk in trans-ethnic cohorts.

Methods: We conducted trans-ethnic fine-mapping of the MHC region for European populations (14,650 cases and 1,288,625 controls) and East Asian populations (7712 cases and 27,372 controls). We adopted a hybrid fine-mapping approach including both HLA genotype imputation of genome-wide association study (GWAS) data and direct imputation of HLA variant risk from the GWAS summary statistics.

Results: Through trans-ethnic MHC fine-mapping, we identified the strongest associations at amino acid position 13 of HLA-DRβ1 (P = 6.0 × 10 ), which explains the majority of the risk in HLA-DRB1. In silico prediction revealed that HLA-DRB1 alleles with histidine at amino acid position 13 (His13) had significantly weaker binding affinity to an α-synuclein epitope than other alleles (P = 9.6 × 10 ). Stepwise conditional analysis suggested additional independent associations at Ala69 in HLA-B (P = 1.0 × 10 ). A subanalysis in Europeans suggested additional independent associations at non-HLA genes in the class III MHC region (EHMT2; P = 2.5 × 10 ).

Conclusions: Our study highlights the shared and distinct genetic features of the MHC region in patients with PD across ethnicities. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453830PMC
August 2021

A case of neurosarcoidosis presenting with multiple cranial neuropathies.

Am J Ophthalmol Case Rep 2020 Sep 27;19:100796. Epub 2020 Jun 27.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Purpose: We report a case of neurosarcoidosis that presented simultaneously with oculomotor nerve palsy, contralateral abducens nerve palsy, and paresthesia of both lower limbs.

Observations: A 69-year-old Japanese woman who suffered from repeated diplopia and lower-limb paresthesia was referred to our hospital. Ophthalmic findings included oculomotor nerve and contralateral abducens nerve palsies. No remarkable abnormalities were detected via enhanced brain magnetic resonance imaging (MRI), chest X-ray, and cerebrospinal fluid analysis. Chest computed tomography (CT) was performed to exclude neoplastic lesions; this revealed right hilar lymphadenopathy, and positron emission tomography MRI showed strong 18-F fluorodeoxyglucose uptake in the hilar lymph node. Biopsy of the lymph node showed non-caseating epithelioid granulomatous tissue, leading to a diagnosis of probable neurosarcoidosis. After the initiation of oral prednisolone treatment, the patient experienced complete remission without any recurrence.

Conclusions And Importance: When examining a patient presenting with multiple cranial neuropathies of unknown cause, neurosarcoidosis should be considered as a differential diagnosis and chest CT should be performed even when the chest X-ray and angiotensin-converting enzyme appears normal.
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http://dx.doi.org/10.1016/j.ajoc.2020.100796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330492PMC
September 2020

Bardet-Biedl syndrome and related disorders in Japan.

J Hum Genet 2020 Oct 25;65(10):847-853. Epub 2020 May 25.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.
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http://dx.doi.org/10.1038/s10038-020-0778-yDOI Listing
October 2020

Genome-wide association study identifies zonisamide responsive gene in Parkinson's disease patients.

J Hum Genet 2020 Aug 1;65(8):693-704. Epub 2020 May 1.

Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Hyogo, Japan.

Long-term treatment of Parkinson's disease (PD) by levodopa leads to motor complication "wearing-off". Zonisamide is a nondopaminergic antiparkinsonian drug that can improve "wearing-off" although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose "off" time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and "off" time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced "off" time (P = 4.85 × 10). Carriers of responsive genotype showed >7-fold decrease in mean "off" time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing "off" time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of "wearing-off" in PD by genotype-guided zonisamide treatment.
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http://dx.doi.org/10.1038/s10038-020-0760-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075945PMC
August 2020

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study.

JAMA Neurol 2020 06;77(6):746-754

Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China.

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).

Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.

Design Setting, And Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria.

Main Outcomes And Measures: Genotypes of common variants, association with disease status, and polygenic risk scores.

Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12).

Conclusions And Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.
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http://dx.doi.org/10.1001/jamaneurol.2020.0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171584PMC
June 2020

Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Brain 2020 04;143(4):1190-1205

Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awaa064DOI Listing
April 2020

Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation.

Acta Neuropathol 2019 03 5;137(3):455-466. Epub 2019 Feb 5.

Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is necessary to examine the early aggregation of AS, i.e., AS oligomers. Here, we adopted a proximity ligation assay (PLA) to examine the distribution of AS oligomers in brain tissue samples from patients with MSA and other diseases. Surprisingly, MSA brains showed a widespread distribution and abundant accumulation of oligomeric AS in neurons as well as oligodendrocytes of the neocortex. In several regions, oligomeric AS signal intensity was higher in cases with MSA than in cases with Parkinson's disease. In contrast to previous studies, AS-PLA revealed abundant AS oligomer accumulation in Purkinje cells in MSA brains, identifying oligomeric AS accumulation as a possible cause of Purkinje cell loss. This wide distribution of AS oligomers in MSA brain neurons has not been described previously and indicates a pathological mechanism of NL in MSA.
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http://dx.doi.org/10.1007/s00401-019-01961-wDOI Listing
March 2019

Altered regulation of serum lysosomal acid hydrolase activities in Parkinson's disease: A potential peripheral biomarker?

Parkinsonism Relat Disord 2019 04 2;61:132-137. Epub 2018 Nov 2.

Department of Neurology, Fujita Health University School of Medicine, Toyoake, Japan. Electronic address:

Introduction: Recent studies have indicated that lysosomal dysfunction contributes to the development of idiopathic Parkinson's disease (PD). It is uncertain whether dysregulation of serum lysosomal acid hydrolase activity exists in sporadic PD patients compared with normal controls (NCs) and parkinsonian syndrome (PS) patients.

Methods: Sporadic PD patients without GBA1 mutations (n = 68) were matched with normal controls (n = 45), and parkinsonian syndrome patients (n = 32) in terms of family history, age, and sex. We measured the activities of lysosomal enzymes, α-galactosidase, β-galactosidase, and β-hexosaminidase and examined the possible correlations between lysosomal acid hydrolase activities with age in NCs, PD, and PS patients.

Results: β-Galactosidase activity was significantly higher in the PD and PS than in the NC group (P < 0.001). The β-galactosidase to α-galactosidase and β-hexosaminidase to β-galactosidase activity ratios were more useful for distinguishing PD and PS patients from NCs (P < 0.0001). Furthermore, α-galactosidase activity was significantly higher in PS patients than both PD and NC groups (p = 0.04). β-Galactosidase and α-galactosidase activities exhibited a statistically significant negative correlation with age in NCs, and β-hexosaminidase activity showed a positive correlation with age in PS. However, PD patients did not show any of these correlations.

Conclusion: Our results suggest the presence of an unknown regulatory mechanism(s) of serum acid hydrolase activities with aging in the normal population and abnormalities in their regulation in PD and PS patients. However, the pattern of dysregulation in these two groups is different. Thus, serum lysosomal acid hydrolase activity can be used as a peripheral biomarker for PD.
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http://dx.doi.org/10.1016/j.parkreldis.2018.10.032DOI Listing
April 2019

In silico drug screening by using genome-wide association study data repurposed dabrafenib, an anti-melanoma drug, for Parkinson's disease.

Hum Mol Genet 2018 11;27(22):3974-3985

Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss. At present, there are no drugs that stop the progression of PD. As with other multifactorial genetic disorders, genome-wide association studies (GWASs) found multiple risk loci for PD, although their clinical significance remains uncertain. Here, we report the identification of candidate drugs for PD by a method using GWAS data and in silico databases. We identified 57 Food and Drug Administration-approved drug families as candidate neuroprotective drugs for PD. Among them, dabrafenib, which is known as a B-Raf kinase inhibitor and is approved for the treatment of malignant melanoma, showed remarkable cytoprotective effects in neurotoxin-treated SH-SY5Y cells and mice. Dabrafenib was found to inhibit apoptosis, and to enhance the phosphorylation of extracellular signal-regulated kinase (ERK), and inhibit the phosphorylation of c-Jun NH2-terminal kinase. Dabrafenib targets B-Raf, and we confirmed a protein-protein interaction between B-Raf and Rit2, which is coded by RIT2, a PD risk gene in Asians and Caucasians. In RIT2-knockout cells, the phosphorylation of ERK was reduced, and dabrafenib treatment improved the ERK phosphorylation. These data indicated that dabrafenib exerts protective effects against neurotoxicity associated with PD. By using animal model, we confirmed the effectiveness of this in silico screening method. Furthermore, our results suggest that this in silico drug screening system is useful in not only neurodegenerative diseases but also other common diseases such as diabetes mellitus and hypertension.
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http://dx.doi.org/10.1093/hmg/ddy279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216208PMC
November 2018

Treatment of a case of severe insulin resistance as a result of a PIK3R1 mutation with a sodium-glucose cotransporter 2 inhibitor.

J Diabetes Investig 2018 Sep 25;9(5):1224-1227. Epub 2018 Mar 25.

Division of Diabetes and Endocrinology, Tokyo, Japan.

A Japanese woman aged in her late 30s with severe insulin resistance and bodily features including a triangular face, prominent forehead, small chin, large and low-set ears, and ocular depression was investigated. A similar phenotype was not observed in other family members with the exception of her son, suggesting that the condition was caused by a de novo mutation that was transmitted from mother to son. Exome analysis showed the presence in the proband and her son of a c.1945C>T mutation in PIK3R1, a common mutation associated with SHORT (short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay) syndrome. Administration of a sodium-glucose cotransporter 2 inhibitor lowered the proband's hemoglobin A level and allowed a reduction in her insulin dose without treatment-related adverse events including ketoacidosis, exaggerated loss of body mass or hypoglycemia. Sodium-glucose cotransporter 2 inhibitors might thus offer an additional option for the treatment of genetic syndromes of severe insulin resistance.
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http://dx.doi.org/10.1111/jdi.12825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123033PMC
September 2018

Japanese de novo mutation diagnosed by exome analysis: A case report.

Neurol Clin Neurosci 2017 07 29;5(4):131-133. Epub 2017 Jun 29.

Division of Neurology Kobe University Graduate School of Medicine Kobe Hyogo Japan.

A 40-year-old Japanese woman presented with slowly progressing parkinsonism in adulthood. She had a history of epilepsy with intellectual disability in childhood. In a head magnetic resonance scan, T2-weighted imaging showed low signal intensity areas in the globus pallidus and the substantia nigra; T1-weighted imaging showed a halo in the nigra. Because the patient's symptoms and history were similar to those of patients with neurodegeneration with brain iron accumulation, we ran an exome analysis to investigate neurodegeneration with brain iron accumulation-associated genes. We identified a c.700 C>T (p.Arg 234*) mutation in exon 9 of the gene, which had not been reported in Japanese patients with beta-propeller protein-associated neurodegeneration (a neurodegeneration with brain iron accumulation subtype). Sanger sequencing confirmed a heterozygous mutation in this patient that was absent in both her parents, so it was judged to be a de novo nonsense mutation.
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http://dx.doi.org/10.1111/ncn3.12132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575553PMC
July 2017

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.

Neurobiol Aging 2017 01 6;49:217.e1-217.e4. Epub 2016 Oct 6.

INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154911PMC
January 2017

A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency.

Am J Med Genet A 2016 Jan 30;170A(1):183-8. Epub 2015 Sep 30.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Glycosylphosphatidylinositol (GPI) anchors tether proteins to the extracellular face of eukaryotic plasma membranes. Defects in the human GPI anchor biosynthetic pathway cause inherited GPI deficiencies (IGDs) characterized by multiple congenital anomalies: dysmorphic faces, developmental delay, hypotonia, and epilepsy. We report the case of a 6-year-old boy with severe psychomotor developmental delay, epilepsy, and decreased granulocyte surface expression of GPI-anchored protein that suggested autosomal recessive GPI deficiency. The case underwent target exome sequencing to screen for IGDs. Target exome sequencing of the proband identified an apparently homozygous c.808T > C (p.Ser270Pro) mutation in PIGN, a gene involved in the GPI anchor biosynthetic pathway. As his parents were expecting another child, genetic carrier screening was conducted for the parents. Direct sequencing of the parents identified a heterozygous c.808T > C PIGN mutation in the father but none in the mother. To identify the mother's mutation, we performed semi-quantitative real-time PCR of the PIGN exons and long PCR, identifying a microdeletion in PIGN (del exons 2-14). The proband had inherited this microdeletion from his mother. Prenatal diagnosis of the fetus revealed that it was a heterozygous carrier of the mother's pathogenic allele. Here, we report a sporadic case of inherited GPI deficiency with a PIGN mutation and the first case of prenatal diagnosis for GPI deficiency.
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http://dx.doi.org/10.1002/ajmg.a.37397DOI Listing
January 2016

The First Nationwide Survey and Genetic Analyses of Bardet-Biedl Syndrome in Japan.

PLoS One 2015 1;10(9):e0136317. Epub 2015 Sep 1.

Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-19. In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while only a few patients with no mutations identified have been reported in Japan. We thus conducted the first nationwide survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7 patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. The latter mutation that resided far from the authentic splicing site was associated with skipping of exon 8. We also found 3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. To our knowledge, a nationwide survey of BBS has not been reported in any other country. In addition, this is the first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically heterogeneous and at least partly shares genetic features with BBS in other countries.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136317PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556711PMC
May 2016

Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.

PLoS One 2015 1;10(7):e0130329. Epub 2015 Jul 1.

Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.

Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130329PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488844PMC
April 2016

Variants associated with Gaucher disease in multiple system atrophy.

Ann Clin Transl Neurol 2015 Apr 28;2(4):417-26. Epub 2015 Feb 28.

Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University Tokyo, Japan.

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series.

Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.

Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)).

Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.
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http://dx.doi.org/10.1002/acn3.185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402086PMC
April 2015

ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout.

Ann Clin Transl Neurol 2015 Mar 19;2(3):302-6. Epub 2015 Jan 19.

Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College Tokorozawa, Japan.

Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high-capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (P = 0.0027), but significantly associated with later Parkinson's disease onset (P = 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease.
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http://dx.doi.org/10.1002/acn3.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369280PMC
March 2015

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.

Lancet Neurol 2015 Mar 4;14(3):274-82. Epub 2015 Feb 4.

Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. Electronic address:

Background: Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes.

Methods: We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles.

Findings: We identified a missense mutation (CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (-9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48-4·24; p=0·0004) and 4·69 (1·59-13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96-1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping.

Interpretation: CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease.

Funding: Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.
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http://dx.doi.org/10.1016/S1474-4422(14)70266-2DOI Listing
March 2015

A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy.

Hum Genome Var 2015 16;2:15022. Epub 2015 Jul 16.

Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine , Kobe, Japan.

Laing distal myopathy (LDM) is an autosomal dominant myopathy that is caused by mutations in the slow/beta cardiac myosin heavy-chain (MYH7) gene. It has been recently reported that LDM presents with a wide range of clinical manifestations. We herein report a large Chinese family with autosomal dominant myopathy. The affected individuals in the family presented with foot drop in early childhood, along with progressive distal and proximal limb weakness. Their characteristic symptoms include scapular winging and scoliosis in the early disease phase and impairment of ambulation in the advanced phase. Although limb-girdle muscle dystrophy (LGMD) was suspected initially, a definite diagnosis could not be reached. As such, we performed linkage analysis and detected four linkage regions, namely 1q23.2-24.1, 14q11.2-12, 15q26.2-26.3 and 17q24.3. Through subsequent whole exome sequencing, we found a de novo p.K1617del causative mutation in the MYH7 gene and diagnosed the disease as LDM. This is the first LDM case in China. Our patients have severe clinical manifestations that mimic LGMD in comparison with the patients with the same mutation reported elsewhere.
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http://dx.doi.org/10.1038/hgv.2015.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785580PMC
April 2016

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

Circ Cardiovasc Genet 2014 Aug 10;7(4):466-74. Epub 2014 Jun 10.

Background: Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.

Methods And Results: We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.

Conclusions: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140998PMC
August 2014

A case of Bardet-Biedl syndrome complicated with intracranial hypertension in a Japanese child.

Brain Dev 2014 Sep 26;36(8):721-4. Epub 2013 Nov 26.

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

Bardet-Biedl syndrome (BBS) is a rare heterogeneous autosomal recessive disorder characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, hypogonadism, learning disability, and renal anomaly that are caused by ciliary dysfunction. 16 genes have been associated with the BBS phenotype. Although recent pathophysiological studies using animal models have shown that ciliary dysfunction may induce hydrocephalus, there have been no reports of BBS with intracranial hypertension. We here describe a 9-year-old Japanese girl who was diagnosed as having BBS and later received renal transplantation due to chronic renal failure. She also exhibited intracranial hypertension, including papilledema and increased intrathecal pressure (260-300 mmH2O), but her brain magnetic resonance imaging was normal. No genetic abnormalities were detected by DNA chip analysis or exome sequencing. Her papilledema improved following administration of acetazolamide. This is the first report of a case of BBS complicated with intracranial hypertension and its treatment.
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http://dx.doi.org/10.1016/j.braindev.2013.10.013DOI Listing
September 2014

YY1 binds to α-synuclein 3'-flanking region SNP and stimulates antisense noncoding RNA expression.

J Hum Genet 2013 Nov 12;58(11):711-9. Epub 2013 Sep 12.

1] Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan [2] Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

α-synuclein (SNCA) is an established susceptibility gene for Parkinson's disease (PD), one of the most common human neurodegenerative disorders. Increased SNCA is considered to lead to PD and dementia with Lewy bodies. Four single-nucleotide polymorphisms (SNPs) in SNCA 3' region were prominently associated with PD among different ethnic groups. To examine how these SNPs influence disease susceptibility, we analyzed their potential effects on SNCA gene expression. We found that rs356219 showed allele-specific features. Gel shift assay using nuclear extracts from SH-SY5Y cells showed binding of one or more proteins to the protective allele, rs356219-A. We purified the rs356219-A-protein complex with DNA affinity beads and identified a bound protein using mass spectrometry. This protein, YY1 (Yin Yang 1), is an ubiquitous transcription factor with multiple functions. We next investigated SNCA expression change in SH-SY5Y cells by YY1 transfection. We also analyzed the expression of antisense noncoding RNA (ncRNA) RP11-115D19.1 in SNCA 3'-flanking region, because rs356219 is located in intron of RP11-115D19.1. Little change was observed in SNCA expression levels; however, RP11-115D19.1 expression was prominently stimulated by YY1. In autopsied cortices, positive correlation was observed among RP11-115D19.1, SNCA and YY1 expression levels, suggesting their functional interactions in vivo. Knockdown of RP11-115D19.1 increased SNCA expression significantly in SH-SY5Y cells, suggesting its repressive effect on SNCA expression. Our findings of the protective allele-specific YY1 and antisense ncRNA raised a novel possible mechanism to regulate SNCA expression.
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http://dx.doi.org/10.1038/jhg.2013.90DOI Listing
November 2013

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

J Med Genet 2012 Nov;49(11):721-6

Department. of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research and DZNE- German Center for Neurodegenerative Diseases, Tübingen, Hoppe-Seyler-Str. 3, Tübingen 72076, Germany.

Background: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive.

Methods And Results: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort.

Conclusions: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
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http://dx.doi.org/10.1136/jmedgenet-2012-101155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488700PMC
November 2012

Association analysis of LRP8 SNP rs3820198 and rs5174 with Parkinson's disease in Han Chinese population.

Neurol Res 2012 Sep;34(7):725-9

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.

Objectives: The single-nucleotide polymorphism (SNP) rs5174 of the low-density lipoprotein receptor-related protein 8 (LRP8) gene has been linked to decreased risk for Parkinson's disease (PD) on Caucasian populations. However, this association has not been proven in Han Chinese populations.

Methods: A total of 378 unrelated Han patients with PD from the Department of Neurology, West China Hospital of Sichuan University and 274 unrelated Han healthy controls (HCs) from the same region were included in this study. SNPs rs5174 and rs3820198 were genotyped using the Sequenom iPLEX Assay technology.

Results: No significant difference was found in the genotype and minor allele frequencies (MAFs) of SNPs rs5174 and rs3820198 between the PD and HC groups, the early-onset PD and HC groups, the late-onset PD and HC groups, as well as the early-onset PD and late-onset PD groups.

Conclusion: This report is the first one on the lack of association of the LRP8 SNPs rs5174 and rs3820198 with PD in Han Chinese population. Together with a Japanese study, the results indicate that the variants within the LRP8 gene do not contribute to the risk of developing PD in Asian populations.
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http://dx.doi.org/10.1179/1743132812Y.0000000075DOI Listing
September 2012

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

Neurology 2012 Aug 11;79(7):659-67. Epub 2012 Jul 11.

Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.

Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.

Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.

Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
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http://dx.doi.org/10.1212/WNL.0b013e318264e353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414661PMC
August 2012

Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.

PLoS Genet 2012 15;8(3):e1002548. Epub 2012 Mar 15.

Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P  =  1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.
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http://dx.doi.org/10.1371/journal.pgen.1002548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305333PMC
September 2012

[Gene for sporadic Parkinson's disease: common disease-common variants].

Rinsho Shinkeigaku 2010 Nov;50(11):864

Division of Neurology, Kobe University Graduate School of Medicine.

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http://dx.doi.org/10.5692/clinicalneurol.50.864DOI Listing
November 2010

Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.

Neurobiol Aging 2011 Nov 22;32(11):2108.e1-5. Epub 2011 Jul 22.

Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tuebingen, Germany.

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.05.024DOI Listing
November 2011

Genetic and clinical analysis in a Chinese parkinsonism-predominant spinocerebellar ataxia type 2 family.

J Hum Genet 2011 Apr 10;56(4):330-4. Epub 2011 Feb 10.

The Department of Medical Genetics, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China.

Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism-predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree.
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http://dx.doi.org/10.1038/jhg.2011.14DOI Listing
April 2011
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