更新于：2024-11-01

ZFYVE19

更新于：2024-11-01

基本信息

别名

Abscission/NoCut checkpoint regulator、ANCHR、FLJ14840

+ [5]

简介

Key regulator of abscission step in cytokinesis: part of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage. Together with CHMP4C, required to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation from ZFYVE19/ANCHR and VPS4 and subsequent abscission.

关联

项与 ZFYVE19 相关的药物

CN117357665

专利挖掘

靶点

ZFYVE19

作用机制-

在研机构

复旦大学附属儿科医院

原研机构

复旦大学附属儿科医院

在研适应症

消化系统疾病

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ZFYVE19 相关的临床结果

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100 项与 ZFYVE19 相关的转化医学

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0 项与 ZFYVE19 相关的专利（医药）

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项与 ZFYVE19 相关的文献（医药）

2024-08-01·Journal of Medical Genetics

ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death

Article

作者: Yang, Jing ; Chi, Hao ; Sheps, Jonathan A ; Wang, Jian-She ; Qiu, Yiling ; Wang, Ren-Xue ; Ling, Victor ; Zhang, Ya-Nan ; Cao, Muqing ; Hao, Chen-Zhi ; Zhang, Xiu-Juan ; Sun, XuXu ; Tang, HongYi ; Luan, Wei-Sha

Background and aimsVariants inZFYVE19underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.MethodsZfyve19knockout (Zfyve19−/−) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients.ZFYVE19knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.ResultsTheZfyve19−/−mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate,Zfyve19−/−mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers fromZfyve19−/−mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.ConclusionsOur findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.

2023-12-01·Human Gene Therapy

Prevention of Portal-Tract Fibrosis in Zfyve19^−/− Mouse Model with Adeno-Associated Virus Vector Delivering ZFYVE19

Article

作者: Tang, Dingyue ; Wang, Li ; Wu, Xia ; Xiao, Xiao ; Zhang, Yanan ; Wang, Jian-She ; Yang, Jing

Zinc finger FYVE-type containing 19 (ZFYVE19) deficiency, caused by biallelic ZFYVE19 complete loss-of-function variants, is a recently identified chronic hepatobiliary disorder characterized by obvious portal-tract fibrosis, increased numbers of bile ducts with malformations, and abnormal levels of serum markers of hepatobiliary injury. As liver-targeted adeno-associated virus (AAV) gene therapy has been used successfully in hepatobiliary diseases, liver-targeted gene therapy has been explored in a mouse model of this disorder. Three ZFYVE19 AAV vectors (AAV-hZFYVE19, AAV-hZFYVE19-m, and AAV-hZFYVE19-co) were constructed and injected into Zfyve19^-/- mice, which were treated with alpha-naphthyl isothiocyanate, a hepatobiliary toxin. Hematoxylin/eosin, immunohistochemical staining, immunofluorescence staining, Sirius Red staining, real-time quantitative PCR, and Western blotting of liver tissue, along with serum hepatobiliary injury marker analyses, were performed to evaluate the effects of gene therapy. AAV-hZFYVE19 decreased serum hepatobiliary injury markers, portal-tract inflammation, ductal hyperplasia, and portal-tract fibrosis in the Zfyve19^-/- model mice most substantially at a relatively low dose (1 × 10¹¹ vg/kg), whereas AAV-hZFYVE19 at a higher dose gradually lost the abovementioned benefits and even caused deterioration at the highest dose of 5 × 10¹² vg/kg. These observations verified the pathogenicity of ZFYVE19 deficiency and suggested that the ZFYVE19 gene needs to function well at an optimal level of expression; both too low and too high a ZFYVE19 expression may be harmful.

2021-12-01·Orphanet Journal of Rare Diseases2区 · 医学

A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant

2区 · 医学

ArticleOA

作者: Vajro, Pietro ; Siano, Maria Anna ; D'Agostino, Ylenia ; Franco, Brunella ; Mandato, Claudia ; Francalanci, Paola ; Brillante, Simona ; Gelzo, Monica ; Morleo, Manuela ; Weisz, Alessandro ; Nazzaro, Lucia ; Rizzo, Francesca

AbstractBackgroundZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation.ResultsA now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities.ConclusionsOur findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.