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Silvia Parisi, Elena V Polishchuk, Simona Allocca, Michela Ciano, Anna Musto, Maria Gallo, Lucia Perone, Giusy Ranucci, Raffaele Iorio, Roman S Polishchuk, Stefano Bonatti
H1069Q substitution represents the most frequent mutation of the copper transporter ATP7B causing Wilson disease in Caucasian population. ATP7B localizes to the Golgi complex in hepatocytes but moves in response to copper overload to the endo-lysosomal compartment to support copper excretion via bile canaliculi. In heterologous or hepatoma-derived cell lines, overexpressed ATP7B-H1069Q is strongly retained in the ER and fails to move to the post-Golgi sites, resulting in toxic copper accumulation. However, this pathogenic mechanism has never been tested in patients' hepatocytes, while animal models recapitulating this form of WD are still lacking...
April 19, 2018: Scientific Reports
Palittiya Sintusek, Eirini Kyrana, Anil Dhawan
Supplemental Digital Content is available in the textABSTRACT OBJECTIVES:: Wilson disease (WD) is a rare inborn error of copper metabolism with diverse manifestations. There has been no study of zinc (Zn), the copper's antagonist, in WD diagnosis and severity so far. Our aims were to evaluate serum Zn in WD and its correlation with the disease severity score (revised WD index). Although the ATP7B mutation analysis is highly accurate for WD diagnosis, it may not be readily available in a resource-limiting setting...
April 17, 2018: Journal of Pediatric Gastroenterology and Nutrition
Gang Liu, Dingyuan Ma, Jian Cheng, Jingjing Zhang, Chunyu Luo, Yun Sun, Ping Hu, Yuguo Wang, Tao Jiang, Zhengfeng Xu
BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation. ATP7B gene mutations lead to ATP7B protein dysfunction, which in turn causes Wilson's disease. CASE PRESENTATION: We describe a male case of Wilson's disease diagnosed at 10 years after routine biochemical test that showed low serum ceruloplasmin levels and Kayser-Fleischer rings in both corneas. Analysis of the ATP7B gene revealed compound heterozygous mutations in the proband, including the reported c...
April 12, 2018: BMC Medical Genetics
Mao Dong Zheng, Nai Dong Wang, Xiao Liang Li, Juan Yan, Jian Hua Tang, Xiu Hua Zhao, Zhihua Zhang
Cisplatin (CDDP) is used in the treatment of non-small cell lung cancer (NSCLC), but due to the development of resistance, the benefit has been limited. Toosendanin (TSN) has shown therapeutic effects on NSCLC; however, the role of TSN on CDDP sensitization in NSCLC remains unknown. The antitumor effects of TSN and CDDP sensitization mediated by TSN were explored. TSN was added in various amounts to measure dose- and time-dependent cytotoxicity. Intracellular CDDP was detected by high-performance liquid chromatography...
April 7, 2018: Journal of Natural Medicines
Go Hun Seo, Yoon-Myung Kim, Seak Hee Oh, Sun Ju Chung, In Hee Choi, Gu-Hwan Kim, Mi-Sun Yum, Jin-Ho Choi, Kyung Mo Kim, Tae-Sung Ko, Beom Hee Lee, Han-Wook Yoo
BACKGROUND: To identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup. METHODS: Detailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients) from 368 unrelated Korean families were analysed. RESULTS: Compared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings and higher serum creatinine levels, and a lower proportion with favourable outcome (62% vs 80%, P<0...
April 4, 2018: Journal of Medical Genetics
Senu Apewokin, Jeannette Y Lee, Julia A Goodwin, Kent D McKelvey, Owen W Stephens, Daohong Zhou, Elizabeth Ann Coleman
BACKGROUND: Clostridium difficile infection (CDI) is the most common hospital-acquired infection. Unfortunately, genes that identify CDI-susceptible patients have not been well described. We performed a genome-wide association study (GWAS) to determine genetic variants associated with the development of CDI. METHODS: A cohort study of Caucasian patients undergoing autologous stem cell transplantation for multiple myeloma was performed. Patients were genotyped using Illumina® Whole Genome Genotyping Infinium chemistry...
March 28, 2018: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Fang Xiao, Yueran Li, Yajun Wan, Min Xue
PURPOSE: Ovarian cancer remains a most malignant female cancer nowadays. The acquisition of chemoresistance to common-used cisplatin-based chemotherapy results in a decreased overall patient survival. The present study is aimed to investigate the role and mechanism by which miR-139/ ATPases7A/B axis modulates the chemoresistance of ovarian cancer to cisplatin-based chemotherapy. METHODS: The expression of miR-139 in cisplatin-sensitive (n = 23) and cisplatin-resistant (n = 14) ovarian cancer tissues and cell lines (CAOV-3 and SNU119) was determined using real-time PCR assays; its effect on ovarian cancer cell chemoresistance to different concentrations of cisplatin was then assessed by measuring the cell viability using MTT assays...
March 28, 2018: Cancer Chemotherapy and Pharmacology
Omid Daneshjoo, Masoud Garshasbi
BACKGROUND: Wilson disease is an autosomal recessive disorder of copper transport and is characterized by excessive accumulation of cellular copper in the liver and other tissues because of impaired biliary copper excretion and disturbed incorporation of copper into ceruloplasmin. Hepatic failure and neuronal degeneration are the major symptoms of Wilson disease. Mutations in the ATP7B gene are the major cause of Wilson disease. CASE PRESENTATION: In this study we have screened one pedigree with several affected members, including a 24-year-old Iranian woman and a 20-year-old Iranian man, who showed psychiatric and neurological symptoms of varying severity, by amplifying the coding regions including exon-intron boundaries with polymerase chain reaction and sequencing...
March 15, 2018: Journal of Medical Case Reports
Emily Reed, Svetlana Lutsenko, Oliver Bandmann
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever...
February 23, 2018: Journal of Neurochemistry
Arnab Gupta, Santanu Das, Kunal Ray
Wilson disease (WD), a Mendelian disorder of copper metabolism caused by mutations in the ATP7B gene, manifests a large spectrum of phenotypic variability. This phenomenon of extensive symptom variation is not frequently associated with a monogenic disorder. We hypothesize that the phenotypic variability in WD is primarily driven by the variations in interacting proteins that regulate the ATP7B function and localization in the cell. Based on existing literature, we delineated a potential molecular mechanism for ATP7B mediated copper transport in the milieu of its interactome, its dysfunction in WD and the resulting variability in the phenotypic manifestation...
March 1, 2018: Metallomics: Integrated Biometal Science
Mayu Nishimuta, Kenta Masui, Tomoko Yamamoto, Yuichi Ikarashi, Katsutoshi Tokushige, Etsuko Hashimoto, Yoji Nagashima, Noriyuki Shibata
We present a case of hepatolenticular degeneration, so-called Wilson's disease (WD), in a 31-year-old Japanese man with broader deposition of copper in the liver, kidney and brain. The liver showed severe cirrhotic changes with macronodular pseudolobule formation, but there was little difference in immunohistochemical expression patterns of the copper transporter ATP7B between the control and present case. In the brain, there were both WD-related lesions such as the scattering of Opalski cells and changes caused by hepatic encephalopathy including the appearance of Alzheimer type II glia...
February 21, 2018: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Thomas Plitz, Lee Boyling
1. WTX101 (bis-choline tetrathiomolybdate) is an investigational copper (Cu)-protein-binding agent developed for the treatment of Wilson disease (WD), a rare genetic disorder caused by mutations in the ATP7B Cu-transporter and resulting in toxic Cu accumulation. 2. Mass balance of a single intravenous WTX101 dose, measured as molybdenum (Mo), was assessed over 168 h in control (Long Evans Agouti [LEA]) and Long-Evans Cinnamon (LEC) rats, a WD model. 3. In LEC rats, Mo was partially excreted (up to 45%); 29% by renal clearance, and faecal clearance, still ongoing at 168 h, accounted for 16%...
February 27, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Anna Członkowska, Maria Rodo, Agata Wierzchowska-Ciok, Lukasz Smolinski, Tomasz Litwin
BACKGROUND & AIMS: In Wilson disease (WD), copper accumulates in the liver and other tissues due to mutations in the ATP7B copper transporter gene. Early and effective anti-copper treatment is crucial. However, routine diagnostic methods based on clinical findings, copper metabolism tests, liver biopsies and DNA analyses do not always provide a conclusive diagnosis. The aim was to evaluate radioactive copper incorporation as a diagnostic test. METHODS: We included cases with a diagnosis of WD supported by radiocopper testing and later, when available, confirmed by DNA analysis...
February 8, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Sarah Guttmann, Gursimran Chandhok, Sara Reinartz Groba, Christoph Niemietz, Vanessa Sauer, Amanda Gomes, Giuliano Ciarimboli, Uwe Karst, Andree Zibert, Hartmut H Schmidt
Platinum-based drugs are first-line compounds in the treatment of many solid cancers. Major obstacles are tumors that become resistant and toxic side effects, both largely due to the expression of transporters that mediate the cellular processing of platinum. In this study, we addressed the establishment of cisplatin resistance in the absence of copper transporter ATP7B that has been previously found to be overexpressed in various resistant cells. Cisplatin sensitivity, induction of apoptosis, drug accumulation, and transporter gene expression were determined in hepatoma cell lines...
January 2, 2018: Oncotarget
Yue-Qin Li, Ji-Ye Yin, Zhao-Qian Liu, Xiang-Ping Li
Platinum-based chemotherapy agents are widely used in the treatment of various solid malignancies. However, their efficacy is limited by drug resistance. Recent studies suggest that copper efflux transporters, which are encoded by ATP7A and ATP7B, play an important role in platinum drug resistance. Over-expressions of ATP7A and ATP7B are observed in multiple cancers. Moreover, their expressions are associated with cancer prognosis and treatment outcomes of platinum-based chemotherapy. In our review, we highlight the roles of ATP7A/7B in platinum drug resistance and cancer progression...
March 2018: IUBMB Life
Siyuan Ye, Tingjun Dai, Bingquan Leng, Lei Tang, Liang Jin, Lili Cao
RATIONALE: Premature osteoarthritis (POA) is a rare condition in Wilson disease (WD). Particularly, when POA is the only complaint of a WD patient for a long time, there would be misdiagnosis or missed diagnosis and then treatment delay. PATIENT CONCERNS AND DIAGNOSIS: Two Chinese Han siblings were diagnosed as WD by corneal K-F rings, laboratory test, and mutation analysis. They presented with isolated POA during the first 2 decades or more of their disease course, and were of missed diagnosis during that long time...
November 2017: Medicine (Baltimore)
Julia Smirnova, Ekaterina Kabin, Ivar Järving, Olga Bragina, Vello Tõugu, Thomas Plitz, Peep Palumaa
Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes copper excretion. Although several de-coppering drugs are currently available, their Cu(I)-binding affinities have not been quantitatively characterized. Here we determined the Cu(I)-binding affinities of five major de-coppering drugs - D-penicillamine, trientine, 2,3-dimercapto-1-propanol, meso-2,3-dimercaptosuccinate and tetrathiomolybdate - by exploring their ability to extract Cu(I) ions from two Cu(I)-binding proteins, the copper chaperone for cytochrome c oxidase, Cox17, and metallothionein...
January 23, 2018: Scientific Reports
Weihua Jiang, Lili Liu, Qiurong Chang, Fengying Xing, Zhengwen Ma, Zhenfu Fang, Jing Zhou, Li Fu, Huiyang Wang, Xingxu Huang, Xuejin Chen, Yao Li, Shangang Li
CRISPR/Cas9 has recently been developed as an efficient genome engineering tool. The rabbit is a suitable animal model for studies of metabolic diseases. In this study, we generated ATP7B site-directed point mutation rabbits to simulate a major mutation type in Asians (p. Arg778Leu) with Wilson disease (WD) by using the CRISPR/Cas9 system combined with single-strand DNA oligonucleotides (ssODNs). The efficiency of the precision point mutation was 52.94% when zygotes were injected 14 hours after HCG treatment and was significantly higher than that of zygotes injected 19 hours after HCG treatment (14...
January 22, 2018: Scientific Reports
Piotr Socha, Wojciech Janczyk, Anil Dhawan, Ulrich Baumann, Lorenzo D'Antiga, Stuart Tanner, Raffaele Iorio, Pietro Vajro, Roderick Houwen, Björn Fischler, Antal Dezsofi, Nedim Hadzic, Loreto Hierro, Jörg Jahnel, Valérie McLin, Valerio Nobili, Francoise Smets, Henkjan J Verkade, Dominique Debray
BACKGROUND: Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene...
February 2018: Journal of Pediatric Gastroenterology and Nutrition
D Huster
Wilson disease is a rare hereditary disorder of copper metabolism. The genetic defect is caused by various mutations in the copper-transporting enzyme ATP7B, located mainly in the liver and brain. Clinical symptoms are highly variable, with any combination of hepatic and/or neurological or psychiatric manifestations. The age of onset varies from early childhood to young adults and can even be manifested in later ages. The clinical diagnosis is based on a combination of clinical, biochemical and molecular markers...
February 2018: Der Internist
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