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Peng Li, Ya-Ling Yin, Tao Guo, Xue-Ying Sun, Hui Ma, Mo-Li Zhu, Fan-Rong Zhao, Ping Xu, Yuan Chen, Guang-Rui Wan, Fan Jiang, Qi-Sheng Peng, Chao Liu, Li-Ying Liu, Shuang-Xi Wang
BACKGROUND: -GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase (eNOS) uncoupling in endothelial dysfunction. MicroRNAs (miR) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. METHODS: -Endothelial function was assessed by measuring acetylcholine- induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by RT-qPCR and fluorescence in situ hybridization...
October 20, 2016: Circulation
M Svetel, A Tomić, M Mijajlović, V Dobričić, I Novaković, T Pekmezović, L Brajković, V S Kostić
BACKGROUND AND PURPOSE: Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder. METHODS: Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs)...
October 12, 2016: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Jasmine Eshragh, Anand Dhruva, Steven M Paul, Bruce A Cooper, Judy Mastick, Deborah Hamolsky, Jon D Levine, Christine Miaskowski, Kord M Kober
CONTEXT: Fatigue is a common problem in oncology patients. Less is known about decrements in energy levels and the mechanisms that underlie both fatigue and energy. OBJECTIVES: In patients with breast cancer, variations in neurotransmitter genes between Lower and Higher Fatigue latent classes and between the Higher and Lower Energy latent classes were evaluated. METHODS: Patients completed assessments prior to and monthly for 6 months following surgery...
October 5, 2016: Journal of Pain and Symptom Management
Anna Potulska-Chromik, Dorota Hoffman-Zacharska, Małgorzata Łukawska, Anna Kostera-Pruszczyk
OBJECTIVE: Dopa-responsive dystonia (DRD) is a rare form of hereditary movement disorder with onset in childhood, characterized by gait difficulties due to postural dystonia with marked improvement after low doses of levodopa. Mutations in the GCH1 gene are the most common cause of DRD, however, in some cases when the disease is associated with parkinsonism mutations in the PARK2 gene may be identified. The aim of this study was to analyze and compare genotype-phenotype correlation. MATERIAL/PARTICIPANTS: Four families with inter- and intrafamilial variability of progressive gait dysfunction due to lower limb dystonia occurring in childhood or adolescence were included in the analysis...
September 12, 2016: Neurologia i Neurochirurgia Polska
Michael Zech, Sylvia Boesch, Angela Jochim, Sandrina Weber, Tobias Meindl, Barbara Schormair, Thomas Wieland, Christian Lunetta, Valeria Sansone, Michael Messner, Joerg Mueller, Andres Ceballos-Baumann, Tim M Strom, Roberto Colombo, Werner Poewe, Bernhard Haslinger, Juliane Winkelmann
BACKGROUND: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia...
September 26, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Khuthala Mnika, Gift D Pule, Collet Dandara, Ambroise Wonkam
Sickle cell disease (SCD) is a blood disease caused by a single nucleotide substitution (T > A) in the beta globin gene on chromosome 11. The single point mutation (Glu6Val) promotes polymerization of hemoglobin S (HbS) and causes sickling of erythrocytes. Vaso-occlusive painful crises are associated with recurrent and long-term use of analgesics/opioids and hydroxyurea (HU) by people living with SCD. The present analysis offers a state-of-the-art expert review of the effectiveness of pharmacogenomics/genetics of pain management in SCD, with specific focus on HU and opioids...
October 2016: Omics: a Journal of Integrative Biology
Ya-Ping Yan, Bo Zhang, Yan-Fang Mao, Zhang-Yu Guo, Jun Tian, Guo-Hua Zhao, Jia-Li Pu, Wei Luo, Zhi-Yuan Ouyang, Bao-Rong Zhang
Dopa-responsive dystonia (DRD) comprises a heterogeneous group of movement disorders. A limited number of studies of Chinese patients with DRD have been reported. In the present study, we investigated the clinical and genetic features of 12 Chinese DRD families. Point mutation analysis of the GTP-cyclohydrolase I (GCH1), tyrosine hydroxylase (TH) and sepiapterin reductase (SPR) genes was conducted by direct sequencing. In addition, multiplex ligation-dependent probe amplification targeting GCH1 and TH was performed in "mutation-free" patients...
October 5, 2016: International Journal of Neuroscience
A Méneret, E Roze
Paroxysmal movement disorders comprise both paroxysmal dyskinesia, characterized by attacks of dystonic and/or choreic movements, and episodic ataxia, defined by attacks of cerebellar ataxia. They may be primary (familial or sporadic) or secondary to an underlying cause. They can be classified according to their phenomenology (kinesigenic, non-kinesigenic or exercise-induced) or their genetic cause. The main genes involved in primary paroxysmal movement disorders include PRRT2, PNKD, SLC2A1, ATP1A3, GCH1, PARK2, ADCY5, CACNA1A and KCNA1...
August 2016: Revue Neurologique
Toshiharu Nagatsu, Ikuko Nagatsu
Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson's disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic L-amino acid decarboxylase (AADC); dopamine β-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD...
November 2016: Journal of Neural Transmission
Hsiang-En Wu, Shelley L Baumgardt, Juan Fang, Mark Paterson, Yanan Liu, Jianhai Du, Yang Shi, Shigang Qiao, Zeljko J Bosnjak, David C Warltier, Judy R Kersten, Zhi-Dong Ge
Diabetic cardiomyopathy increases the risk of heart failure and death. At present, there are no effective approaches to preventing its development in the clinic. Here we report that reduction of cardiac GTP cyclohydrolase 1 (GCH1) degradation by genetic and pharmacological approaches protects the heart against diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in C57BL/6 wild-type mice and transgenic mice with cardiomyocyte-specific overexpression of GCH1 with streptozotocin, and control animals were given citrate buffer...
2016: Scientific Reports
Aina Rengmark, Lasse Pihlstrøm, Jan Linder, Lars Forsgren, Mathias Toft
BACKGROUND: The causes of Parkinson's disease (PD) are unknown in the majority of patients. The GCH1 gene encodes GTP-cyclohydrolase I, an important enzyme in dopamine synthesis. Co-occurrence of dopa-responsive dystonia (DRD) and a PD phenotype has been reported in families with GCH1 mutations. Recently, rare coding variants in GCH1 were found to be enriched in PD patients, indicating a role for the enzyme in the neurodegenerative process. METHODS: To further elucidate the contribution of GCH1 mutations to sporadic PD, we examined its coding exons in a targeted deep sequencing study of 509 PD patients (mean age at onset 56...
August 2016: Parkinsonism & related Disorders
Aloysius Domingo, Roberto Erro, Katja Lohmann
Dystonia is a genetically heterogenous disease and a prototype disorder where next-generation sequencing has facilitated the identification of new pathogenic genes. This includes the first two genes linked to recessively inherited isolated dystonia, that is, HPCA (hippocalcin) and COL6A3 (collagen VI alpha 3). These genes are proposed to underlie cases of the so-called DYT2-like dystonia, while also reiterating two distinct pathways in dystonia pathogenesis. First, deficiency in HPCA function is thought to alter calcium homeostasis, a mechanism that has previously been forwarded for CACNA1A and ANO3...
April 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Steven Z George, Samuel S Wu, Margaret R Wallace, Michael W Moser, Thomas W Wright, Kevin W Farmer, Warren H Greenfield, Yunfeng Dai, Hua Li, Roger B Fillingim
OBJECTIVE: The current study identified novel combinations of genetic and psychological factors that predicted 12-month post-operative pain and disability outcomes following arthroscopic shoulder surgery. METHODS: A prospective pre-surgical cohort (n = 150) was recruited to complete validated psychological questionnaires and have their DNA collected from saliva. DNA was genotyped for a priori selected genes involved with pain modulation (ADRB2, OPRM1, AVPR1A, GCH1, and KCNS1) and inflammation (IL1B, TNF/LTA, and IL6)...
March 4, 2016: Arthritis Care & Research
Katja Zschiebsch, Caroline Fischer, Geethanjali Pickert, Annett Häussler, Heinfried Radeke, Sabine Grösch, Nerea Ferreirós, Gerd Geisslinger, Ernst R Werner, Irmgard Tegeder
BACKGROUND AND AIMS: Guanosine triphosphate cyclohydrolase [GCH1] governs the production of the enzyme cofactor tetrahydrobiopterin [BH4] which is essential for biogenic amine synthesis, lipid metabolism via alkylglycerol monooxygenase [AGMO], and redox coupling of nitric oxide synthases [NOSs]. Inflammation-evoked unequal regulation of GCH1 and NOS or AGMO may cause redox stress and lipid imbalances. METHODS: The present study assessed potential therapeutic effects of rebalancing these systems with BH4 in experimental colitis in mice...
August 2016: Journal of Crohn's & Colitis
Hua-ping Zhang, Jia-hui Zhao, Hai-xia Yu, Dong-xing Guo
Endothelial nitric oxidase synthase (eNOS) uncoupling plays a causal role in endothelial dysfunction in atherosclerosis. Genistein consumption has been associated with the prevention of atherosclerosis. However, the effect of genistein on eNOS uncoupling has not been reported. A model of oxidized low-density lipoprotein (ox-LDL)-induced injury on human umbilical vein endothelial cells (HUVECs) was established to evaluate the effect of genistein on eNOS uncoupling. We investigated the effect of genistein on NADPH oxidase-dependent superoxide production, NOX4 expression, BH4 synthesis and oxidation, the expression of GTP cyclohydrolase 1 (GCH1) and dihydrofolate reductase (DHFR)...
March 2016: Environmental Toxicology and Pharmacology
Chiung-Mei Chen, Yi-Chun Chen, Mu-Chun Chiang, Hon-Chung Fung, Kuo-Hsuan Chang, Guey-Jen Lee-Chen, Yih-Ru Wu
Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet to be examined in PD patients in Chinese or Asian population. Because ethnic-specific effect is an important concern for GWAS analysis, we genotyped single-nucleotide polymorphisms in the new genetic loci, GCH1 (rs11158026), SIPA1L2 (rs10797576), VPS13C (rs2414739), and MIR4697 (rs329648), to investigate their associations with risk of PD in Taiwan...
March 2016: Neurobiology of Aging
Ling Wang, Lan Cheng, Nan-Nan Li, Wen-Juan Yu, Xiao-Yi Sun, Rong Peng
Large-scale meta-analysis of genome-wide association data has identified six new risk loci (SIPA1L2, INPP5F, MIR4697, GCH1, VPS13C, and DDRGK1) for Parkinson's disease (PD). However, the characteristics of those loci in a Han Chinese population from mainland China are unknown. We examined genetic associations of VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 with PD susceptibility in a Han Chinese population of 1028 sporadic PD patients and 1109 healthy controls. All subjects were genotyped for these loci using the Sequenom iPLEX Assay...
April 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Sara Bandrés-Ciga, Niccolò Emmanuele Mencacci, Raquel Durán, Francisco Javier Barrero, Francisco Escamilla-Sevilla, Sarah Morgan, Jason Hehir, Francisco Vives, John Hardy, Alan M Pittman
To date, a large spectrum of genetic variants has been related to familial and sporadic Parkinson's disease (PD) in diverse populations worldwide. However, very little is known about the genetic landscape of PD in Southern Spain, despite its particular genetic landscape coming from multiple historical migrations. We included 134 PD patients in this study, of which 97 individuals were diagnosed with late-onset sporadic PD (LOPD), 28 with early-onset sporadic PD (EOPD), and 9 with familial PD (FPD). Genetic analysis was performed through a next-generation sequencing panel to screen 8 PD-related genes (LRRK2, SNCA, PARKIN, PINK1, DJ-1, VPS35, GBA, and GCH1) in EOPD and FPD groups and direct Sanger sequencing of GBA exons 8-11 and LRRK2 exons 31 and 41 in the LOPD group...
January 2016: Neurobiology of Aging
W T Shi, C Y Cai, M S Li, C Ling, W D Li
We identified three novel mutations of the GTP cyclohydrolase 1 (GCH1) gene in patients with familial dopa-responsive dystonia (DRD), but were unable to identify meaningful sporadic mutations in patients with no obvious family DRD background. To investigate whether GCH1 regional deletions account for the etiology of DRD, we screened for heterozygous exonic deletions in DRD families and in patients with sporadic DRD. Multiple ligation-dependent probe amplification analysis and quantitative real-time polymerase chain reaction amplification was performed in all members of our DRD cohort and in controls to detect exonic deletions in GCH1, tyrosine hydroxylase, and the epsilon-sarcoglycan-encoding (SGCE) genes...
2015: Genetics and Molecular Research: GMR
Fatimah Dabo Pettersson, Charlotte Hellgren, Fred Nyberg, Helena Åkerud, Inger Sundström-Poromaa
Relatively little is known about mental health and labor pain. The aim of this study was to assess if self-rated antenatal depressed mood and anxiety are associated with pain-related behaviors and self-reported labor pain. We also wanted to replicate our previous finding of altered labor pain behavior in carriers of a specific guanosine triphosphate cyclohydrolase 1 gene (GCH1) haplotype. Ninety-nine women in gestational weeks 37 to 40 filled out questionnaires on depression and anxiety symptoms and later rated their labor pain by use of visual analog scales...
February 2016: Archives of Women's Mental Health
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