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https://www.readbyqxmd.com/read/30405245/the-metabolite-bh4-controls-t-cell-proliferation-in-autoimmunity-and-cancer
#1
Shane J F Cronin, Corey Seehus, Adelheid Weidinger, Sebastien Talbot, Sonja Reissig, Markus Seifert, Yann Pierson, Eileen McNeill, Maria Serena Longhi, Bruna Lenfers Turnes, Taras Kreslavsky, Melanie Kogler, David Hoffmann, Melita Ticevic, Débora da Luz Scheffer, Luigi Tortola, Domagoj Cikes, Alexander Jais, Manu Rangachari, Shuan Rao, Magdalena Paolino, Maria Novatchkova, Martin Aichinger, Lee Barrett, Alban Latremoliere, Gerald Wirnsberger, Guenther Lametschwandtner, Meinrad Busslinger, Stephen Zicha, Alexandra Latini, Simon C Robson, Ari Waisman, Nick Andrews, Michael Costigan, Keith M Channon, Guenter Weiss, Andrey V Kozlov, Mark Tebbe, Kai Johnsson, Clifford J Woolf, Josef M Penninger
Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain1,2 . Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells...
November 7, 2018: Nature
https://www.readbyqxmd.com/read/30314816/common-and-rare-gch1-variants-are-associated-with-parkinson-s-disease
#2
Uladzislau Rudakou, Bouchra Ouled Amar Bencheikh, Jennifer A Ruskey, Lynne Krohn, Sandra B Laurent, Dan Spiegelman, Christopher Liong, Stanley Fahn, Cheryl Waters, Oury Monchi, Edward A Fon, Yves Dauvilliers, Roy N Alcalay, Nicolas Dupré, Ziv Gan-Or
GCH1 encodes the enzyme guanosine triphospahte (GTP) cyclohydrolase 1, essential for dopamine synthesis in nigrostriatal cells, and rare mutations in GCH1 may lead to Dopa-responsive dystonia (DRD). While GCH1 is implicated in genomewide association studies in Parkinson's disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the present study, GCH1 and its 5' and 3' untranslated regions were sequenced in 1113 patients with PD and 1111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was performed...
September 15, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/30265714/amplification-of-gtp-cyclohydrolase-1-gene-in-plasmodium-falciparum-isolates-with-the-quadruple-mutant-of-dihydrofolate-reductase-and-dihydropteroate-synthase-genes-in-ghana
#3
Musah Osei, Felix Ansah, Sena A Matrevi, Kwaku P Asante, Gordon A Awandare, Neils B Quashie, Nancy O Duah
Sulfadoxine-pyrimethamine (SP) is used as malaria chemoprophylaxis for pregnant women and children in Ghana. Plasmodium falciparum resistance to SP is linked to mutations in the dihydropteroate synthase gene (pfdhps), dihydrofolate reductase gene (pfdhfr) and amplification of GTP cyclohydrolase 1 (pfgch1) gene. The pfgch1 duplication is associated with pfdhfr L164, a crucial mutant for high level pyrimethamine resistance which is rare in Ghana. The presence of amplified pfgch1 in Ghanaian isolates could be an indicator of the evolution of the L164 mutant...
2018: PloS One
https://www.readbyqxmd.com/read/30245141/the-genetic-landscape-of-parkinson-s-disease
#4
REVIEW
A Lunati, S Lesage, A Brice
The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B...
September 20, 2018: Revue Neurologique
https://www.readbyqxmd.com/read/30237473/dystonia
#5
REVIEW
Bettina Balint, Niccolò E Mencacci, Enza Maria Valente, Antonio Pisani, John Rothwell, Joseph Jankovic, Marie Vidailhet, Kailash P Bhatia
Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. Dystonia can be the manifesting neurological sign of many disorders, either in isolation (isolated dystonia) or with additional signs (combined dystonia). The main focus of this Primer is forms of isolated dystonia of idiopathic or genetic aetiology. These disorders differ in manifestations and severity but can affect all age groups and lead to substantial disability and impaired quality of life...
September 20, 2018: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/30085331/exendin%C3%A2-4-reverses-endothelial-dysfunction-in-mice-fed-a-high%C3%A2-cholesterol-diet-by-a-gtp-cyclohydrolase%C3%A2-1-tetrahydrobiopterin-pathway
#6
Zhiqi Tang, Lijuan Liu, Yujie Guo, Guoxiong Deng, Meixiang Chen, Jinru Wei
The present study examined whether exendin‑4 (Ex4) can improve the endothelial dysfunction of apolipoprotein E knockout (APOE‑KO) mice fed a high‑cholesterol diet and the potential mechanism by which it acts. Genetically wild‑type (WT) C57BL/6 mice and APOE‑KO mice of C57BL/6 background, were each randomly assigned to receive either Ex4 treatment (Ex4‑treated, for 8 weeks) or not (control). The 4 groups were fed the same high‑cholesterol diet for 8 weeks. The following were measured at the end of the eighth week: Endothelium‑dependent vasodilation of the arteries; plasma nitric oxide (NO) and metabolic index; levels of endothelial NO synthase (eNOS); phosphorylated eNOS (p‑eNOS; Ser‑1,177); guanosine triphosphate cyclohydrolase‑1 (GCH1); and tetrahydrobiopterin (THB)...
September 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/30031848/genetic-variants-of-gch1-associate-with-chronic-and-acute-crisis-pain-in-african-americans-with-sickle-cell-disease
#7
Nilanjana Sadhu, Ellie H Jhun, Yingwei Yao, Ying He, Robert E Molokie, Diana J Wilkie, Zaijie Jim Wang
The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = -3.76, p = 0.037; dominant model: B = -5.61, p = 0.021) and rs3783641 (additive model: incident rate ratio [IRR] = 1...
October 2018: Experimental Hematology
https://www.readbyqxmd.com/read/30001213/molecular-genetics-of-tetrahydrobiopterin-deficiency-in-chinese-patients
#8
Nana Li, Ping Yu, Bin Rao, Ying Deng, Yixiong Guo, Yushan Huang, Lijie Ding, Jun Zhu, Huanming Yang, Jian Wang, Jian Guo, Fang Chen, Zhen Liu
Background The overall incidence of hyperphenylalaninemia (HPA) in China is 1:11,763, with tetrahydrobiopterin (BH4) deficiency accounting for 8.55% of patients with HPA in the mainland. Much progress has been made in the diagnosis and treatment of BH4 deficiency with the introduction of neonatal screening in China. However, the screening rate is still low and screening is not universally available. Methods A total of 44 BH4-deficient patients were enrolled in this study, of which 39 were diagnosed with BH4 deficiency, while the remaining five showed typical characteristics of BH4 deficiency at a later period...
August 28, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
https://www.readbyqxmd.com/read/29995172/human-tyrosine-hydroxylase-in-parkinson-s-disease-and-in-related-disorders
#9
REVIEW
Toshiharu Nagatsu, Akira Nakashima, Hiroshi Ichinose, Kazuto Kobayashi
Parkinson's disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline)...
July 11, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29963647/l-phenylalanine-restores-vascular-function-in-spontaneously-hypertensive-rats-through-activation-of-the-gch1-gfrp-complex
#10
Lamia Heikal, Anna Starr, Dania Hussein, Jesus Prieto-Lloret, Phil Aaronson, Lea Ann Dailey, Manasi Nandi
Reduced nitric oxide (NO) bioavailability correlates with impaired cardiovascular function. NO is extremely labile and has been challenging to develop as a therapeutic agent. However, NO bioavailability could be enhanced by pharmacologically targeting endogenous NO regulatory pathways. Tetrahydrobiopterin, an essential cofactor for NO production, is synthesized by GTP cyclohydrolase-1 (GCH1), which complexes with GCH1 feedback regulatory protein (GFRP). The dietary amino acid l-phenylalanine activates this complex, elevating vascular BH4 ...
June 2018: JACC. Basic to Translational Science
https://www.readbyqxmd.com/read/29953636/comparative-analysis-of-the-blood-transcriptomes-between-wolves-and-dogs
#11
COMPARATIVE STUDY
X Yang, H Zhang, J Shang, G Liu, T Xia, C Zhao, G Sun, H Dou
Dogs were domesticated by human and originated from wolves. Their evolutionary relationships have attracted much scientific interest due to their genetic affinity but different habitats. To identify the differences between dogs and wolves associated with domestication, we analysed the blood transcriptomes of wolves and dogs by RNA-Seq. We obtained a total of 30.87 Gb of raw reads from two dogs and three wolves using RNA-Seq technology. Comparisons of the wolf and dog transcriptomes revealed 524 genes differentially expressed genes between them...
August 2018: Animal Genetics
https://www.readbyqxmd.com/read/29948246/gch1-mutations-in-dopa-responsive-dystonia-and-parkinson-s-disease
#12
Hiroyo Yoshino, Kenya Nishioka, Yuanzhe Li, Yutaka Oji, Genko Oyama, Taku Hatano, Yutaka Machida, Yasushi Shimo, Arisa Hayashida, Aya Ikeda, Kaoru Mogushi, Yasuro Shibagaki, Ai Hosaka, Hiroshi Iwanaga, Junko Fujitake, Takekazu Ohi, Daigo Miyazaki, Yoshiki Sekijima, Mitsuaki Oki, Hirofumi Kusaka, Ken-Ichi Fujimoto, Yoshikazu Ugawa, Manabu Funayama, Nobutaka Hattori
Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123 I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans...
August 2018: Journal of Neurology
https://www.readbyqxmd.com/read/29913814/snp-in-tnf%C3%AE-t308g-is-predictive-for-persistent-postoperative-pain-following-inguinal-hernia-surgery
#13
Maija Kalliomäki, Anne-Li Lind, Alfhild Grönbladh, Ulf Gunnarsson, Gabriel Sandblom, Torsten Gordh, Fred Nyberg
Aim of investigation Persistent postoperative pain of some extent is seen in about 20% of patients after surgical operations, while 80% heal without chronic pain. The type of chronic pain that arises is mainly neuropathic, and is suggested to be in part regulated by genetic factors. In order to study the possible involvement of some candidate genes suggested to be involved in the processing of pain (BDNF, CACNA2D2, ORPM1, GRIK 3, GCH1 and TNF-α ), we performed a genetic association study in a well characterized clinical material of patients that had undergone surgery for inguinal hernia (n = 189)...
December 29, 2017: Scandinavian Journal of Pain
https://www.readbyqxmd.com/read/29913682/gch1-variants-tetrahydrobiopterin-and-their-effects-on-pain-sensitivity
#14
REVIEW
Arafat Nasser, Lisbeth Birk Møller
Background A great proportion of the variation in pain experience and chronicity is caused by heritable factors. Within the last decades several candidate genes have been discovered either increasing or decreasing pain sensitivity or the risk of chronic pain in humans. One of the most studied genes is the GCH1 gene coding for the enzyme GTP cyclohydrolase 1 (GCH1). GCH1 catalyses the initial and rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4). The main function of BH4 is regulation of monoamine and nitric oxide biosynthesis, all involved in nociceptive signalling...
April 1, 2014: Scandinavian Journal of Pain
https://www.readbyqxmd.com/read/29844152/endothelial-cell-tetrahydrobiopterin-modulates-sensitivity-to-ang-angiotensin-ii-induced-vascular-remodeling-blood-pressure-and-abdominal-aortic-aneurysm
#15
Surawee Chuaiphichai, Victoria S Rashbrook, Ashley B Hale, Lucy Trelfa, Jyoti Patel, Eileen McNeill, Craig A Lygate, Keith M Channon, Gillian Douglas
GTPCH (GTP cyclohydrolase 1, encoded by Gch1 ) is required for the synthesis of tetrahydrobiopterin; a critical regulator of endothelial NO synthase function. We have previously shown that mice with selective loss of Gch1 in endothelial cells have mild vascular dysfunction, but the consequences of endothelial cell tetrahydrobiopterin deficiency in vascular disease pathogenesis are unknown. We investigated the pathological consequence of Ang (angiotensin) II infusion in endothelial cell Gch1 deficient ( Gch1 fl/fl Tie2cre) mice...
July 2018: Hypertension
https://www.readbyqxmd.com/read/29801903/targeted-gene-capture-sequencing-in-diagnosis-of-dystonia-patients
#16
Jun Ma, Lin Wang, Ying-Mai Yang, Xin-Hua Wan
BACKGROUND: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Molecular diagnosis is important for an accurate diagnosis of dystonia. Targeted gene capture sequencing has been an effective method for screening multiple candidate genes simultaneously. This method, however, has been rarely reported to be used with dystonia patients. OBJECTIVES AND METHODS: To assess the effectiveness of the targeted gene capture sequencing in dystonia, we performed custom target gene capture followed by next-generation sequencing in dystonia patients from China...
July 15, 2018: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/29789398/microrna-133a-impairs-perfusion-recovery-after-hindlimb-ischemia-in-diabetic-mice
#17
Lingdan Chen, Chunli Liu, Dejun Sun, Tao Wang, Li Zhao, Wenli Chen, Mingjie Yuan, Jian Wang, Wenju Lu
Objective: Peripheral arterial disease (PAD) patients with diabetes mellitus suffer from impaired neovascularization after ischemia which results in poorer outcomes. MicroRNA (miR)-133a is excessively expressed in endothelial cells under diabetic conditions. Here, we test whether diabetes-induced miR-133a up-regulation is involved in the impaired capability of neovascularization in experimental PAD models. Methods and results: MiR-133a level was measured by quantitative RT-PCR and showed a higher expression level in the ischemic muscle from diabetic mice when compared with nondiabetic mice...
August 31, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29724574/study-of-gch1-and-th-genes-in-chinese-patients-with-parkinson-s-disease
#18
Ya-Ping Yan, Bo Zhang, Ting Shen, Xiao-Li Si, Zhang-Yu Guo, Jun Tian, Cong-Ying Xu, Bao-Rong Zhang
Whole-exome sequencing of Parkinson's disease (PD) patients has revealed that the frequency of GTP-cyclohydrolase I (GCH1) variants was significantly higher in patients than in controls. GCH1 rs11158026 was also found to increase the risk of PD. To investigate genetic contribution of dopa-responsive dystonia-related genes to PD, GCH1, and tyrosine hydroxylase (TH) were tested in PD patients. A total of 859 study subjects comprising 421 patients with PD and 438 controls were recruited. For GCH1 gene, one known variant (c...
August 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29682797/mouse-urothelial-genes-associated-with-voiding-behavior-changes-after-ovariectomy-and-bladder-lipopolysaccharide-exposure
#19
Marian Acevedo-Alvarez, Judy Yeh, Lery Alvarez-Lugo, Ming Lu, Nitin Sukumar, Warren G Hill, Toby C Chai
AIMS: Symptoms from overactive bladder (OAB) and cystitis secondary to urinary tract infection (UTI) can be similar in post-menopausal women. Effects of ovariectomy (OVX) on voiding behavior after lipopolysaccharide (LPS) intravesical exposure (surrogate for cystitis) in mice were measured. Urothelial genes associated with micturition changes were identified. METHODS: Female C57BL6/J mice underwent OVX or sham surgeries (n = 10 for each). Voiding spot assays (VSA) were performed prior to surgery, 4 weeks post-surgery, and each time after 3 consecutive days of transurethral instillation of LPS...
November 2018: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/29622492/association-analyses-of-variants-of-sipa1l2-mir4697-gch1-vps13c-and-ddrgk1-with-parkinson-s-disease-in-east-asians
#20
Ming Zou, Rui Li, Jian-Yong Wang, Ke Wang, Ya-Nan Wang, Yang Li, Fei-Xue Ji, Sheng-Nan Sun, Shi-Shi Huang, Hui-Hui Fan, Chen-Ping Huang, Xiong Zhang, Jian-Hong Zhu
A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls...
August 2018: Neurobiology of Aging
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