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Lukas Schwintzer, Eva Aguado Roca, Meike Broemer
TRIAD3/RNF216 is a ubiquitin ligase of the RING-in-between-RING family. Recent publications identified TRIAD3 mutations in patients with neurological diseases, including Gordon Holmes syndrome and Huntington-like disorder. To understand the functional relevance of these disease-associated mutations, we have tested the ubiquitin ligase activity of mutated TRIAD3 in vitro. Several of these point mutations completely abrogated TRIAD3's catalytic activity. Using mass spectrometry, we identified new TRIAD3-interacting proteins/substrates from mouse brain lysate, which provide a new link between TRIAD3 and processes involving clathrin-mediated endocytosis...
2019: Cell Death Discovery
Fangfang Li, Dengfeng Li, Huadie Liu, Bei-Bei Cao, Fang Jiang, Dan-Na Chen, Jia-Da Li
RNF216 , encoding an E3 ubiquitin ligase, has been identified as a causative gene for Gordon Holmes syndrome, characterized by ataxia, dementia, and hypogonadotropic hypogonadism. However, it is still elusive how deficiency in RNF216 leads to hypogonadotropic hypogonadism. In this study, by using GN11 immature GnRH neuronal cell line, we demonstrated an important role of RNF216 in the GnRH neuron migration. RNA interference of RNF216 inhibited GN11 cell migration, but had no effect on the proliferation of GN11 cells or GnRH expression...
2019: Frontiers in Endocrinology
Ashley F Melnick, Yuen Gao, Jiali Liu, Deqiang Ding, Alicia Predom, Catherine Kelly, Rex A Hess, Chen Chen
Ring finger protein 216 (RNF216) belongs to the RING family of E3 ubiquitin ligases that are involved in cellular protein degradation. Mutations in human Rnf216 gene have been identified in Gordon Holmes syndrome, which is defined by ataxia, dementia and hypogonadotropism. However, the gene function of Rnf216 in mammalian species remains unknown. Here, we show that targeted deletion of Rnf216 in mice results in disruption in spermatogenesis and male infertility. RNF216 is not required for female fertility. These findings reveal an essential function of RNF216 in spermatogenesis and male fertility and suggest a critical role for RNF216 in human gonadal development...
January 15, 2019: Biology of Reproduction
Young Hun Kim, Man Sup Kwak, Jae Min Shin, Ria Aryani Hayuningtyas, Ji Eun Choi, Jeon-Soo Shin
Autophagy is a central intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles, and regulation of autophagy is essential for homeostasis. HMGB1 is an important sepsis mediator when secreted and also functions as an inducer of autophagy by binding to Beclin 1. In this study, we studied the effect of inflachromene (ICM), a novel HMGB1 secretion inhibitor, on autophagy. ICM inhibited autophagy by inhibiting nucleocytoplasmic translocation of HMGB1 and by increasing Beclin 1 ubiquitylation for degradation by enhancing the interaction between Beclin 1 and E3 ubiquitin ligase RNF216...
February 20, 2018: Journal of Cell Science
Orazio Palumbo, Maria Accadia, Pietro Palumbo, Maria Pia Leone, Antonio Scorrano, Teresa Palladino, Raffaella Stallone, Maria Clara Bonaglia, Massimo Carella
Non-recurrent microdeletion (≤2 Mb in size) in 7p22.1 is a rarely described cytogenetic aberration, only recently reported in patients with developmental delay/intellectual disability, short stature and microcephaly. The size of the deletions ranged from 0.37 to 1.5 Mb, and reported genotype-phenotype correlations identified a minimum deleted region of 0.37 Mb involving the FBLX18, ACTB, FSCN1, RNF216 and ZNF815P genes. The authors suggested that deletion of ACTB, which encodes β-actin, an essential component of the cytoskeleton, could be responsible for the clinical features observed in the patients with a 7p22...
May 2018: European Journal of Medical Genetics
Rui Guan, Shengyun Cai, Mingjuan Sun, Mingjuan Xu
Ovarian cancer is the most common gynecological malignant cancer in female genitalia. Dysregulation or dysfunction of microRNAs (miRs) contribute to cancer development. The role of miR-520b in ovarian cancer remains unclear. The present study investigated the role of miR-520b in ovarian cancer and determined that the expression levels of miR-520b in ovarian cancer tissues and cell lines were upregulated. By contrast, reverse transcription-quantitative polymerase chain reaction and immunohistochemistry revealed that the mRNA and protein expression levels of ring finger protein 216 (RNF216) were downregulated in ovarian cancer, indicating that there was a negative correlation between miR-520b and RNF216...
September 2017: Oncology Letters
Jonathan C Schisler, Cam Patterson, Monte S Willis
AIM: Hereditary ataxias are characterized by a slowly progressive loss of gait, hand, speech, and eye coordination and cerebellar atrophy. A subset of these, including hypogonadism, are inherited as autosomal recessive traits involving coding mutations of genes involved in ubiquitination including RNF216, OTUD4, and STUB1. Cerebellar CHIPopathy (MIM 615768) is a form of autosomal recessive spinocerebellar ataxia (SCAR16) and when accompanied with hypogonadism, clinically resembles the Gordon Holmes Syndrome (GHS)...
April 2016: African Journal of Cellular Pathology
Motofumi Kumazoe, Yuki Nakamura, Mai Yamashita, Takashi Suzuki, Kanako Takamatsu, Yuhui Huang, Jaehoon Bae, Shuya Yamashita, Motoki Murata, Shuhei Yamada, Yuki Shinoda, Wataru Yamaguchi, Yui Toyoda, Hirofumi Tachibana
Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3- O -gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation...
March 10, 2017: Journal of Biological Chemistry
Nilofer Husain, Qiang Yuan, Yi-Chun Yen, Olga Pletnikova, Dong Qianying Sally, Paul Worley, Zoë Bichler, H Shawn Je
Multiple loss-of-function mutations in TRIAD3 (a.k.a. RNF216) have recently been identified in patients suffering from Gordon Holmes syndrome (GHS), characterized by cognitive decline, dementia, and movement disorders. TRIAD3A is an E3 ubiquitin ligase that recognizes and facilitates the ubiquitination of its target for degradation by the ubiquitin-proteasome system (UPS). Here, we demonstrate that two of these missense substitutions in TRIAD3 (R660C and R694C) could not regulate the degradation of their neuronal target, activity-regulated cytoskeletal-associated protein (Arc/Arg 3...
April 2017: Aging Cell
Luisa Ronzoni, Francesca Sofia Grassi, Lidia Pezzani, Arianna Tucci, Marco Baccarin, Susanna Esposito, Donatella Milani
7p22.1 microduplication syndrome is mainly characterized by developmental and speech delay, craniofacial dysmorphisms and skeletal abnormalities. The minimal critical region includes two OMIM genes: ACTB and RNF216. Here, we report on a girl carrying the smallest 7p22.1 microduplication detected to date, contributing to the delineation of the clinical phenotype of the 7p22.1 duplication syndrome and to the refinement of the minimal critical region. Our patient shares several major features of the 7p22.1 duplication syndrome, including craniofacial dysmorphisms and speech and motor delay, but she also presents with renal anomalies...
February 2017: European Journal of Medical Genetics
Keiko Shimojima, Satoshi Narai, Masami Togawa, Tomotsune Doumoto, Noriko Sangu, Olivier M Vanakker, Anne de Paepe, Matthew Edwards, John Whitehall, Sally Brescianini, Florence Petit, Joris Andrieux, Toshiyuki Yamamoto
There are no published reports of patients harboring microdeletions involving the 7p22.1 region. Although 7p22.1 microdeletions are rare, some reports have shown microduplications encompassing this region. In this study, we report five patients with overlapping deletions of the 7p22.1 region. The patients exhibited clinical similarities including non-specific developmental delay, short stature, microcephaly, and other distinctive features. The shortest region of overlap within the 7p22.1 region includes five genes, FBXL18, ACTB, FSCN1, RNF216, and ZNF815P...
October 2016: European Journal of Medical Genetics
Mohammed Alqwaifly, Saeed Bohlega
Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with RNF216 mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in RNF216 that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G>A)...
June 15, 2016: Neurology International
Hui Wang, Yanan Wang, Liu Qian, Xue Wang, Hailiang Gu, Xiaoqiang Dong, Shiqian Huang, Min Jin, Hailiang Ge, Congfeng Xu, Yanyun Zhang
Originally identified as an E3 ligase regulating toll-like receptor (TLR) signaling, ring finger protein 216 (RNF216) also plays an essential role in autophagy, which is fundamental to cellular homeostasis. Autophagy dysfunction leads to an array of pathological events, including tumor formation. In this study, we found that RNF216 was upregulated in human colorectal cancer (CRC) tissues and cell lines, and was associated with progression of CRC. RNF216 promoted CRC cell proliferation and migration in vitro and in vivo, largely by enhancing proteasomal degradation of BECN1, a key autophagy regulator and tumor suppressor...
August 9, 2016: Oncotarget
Alexandra Richard, Jean-Christophe Corvol, Rabab Debs, Pauline Reach, Khadija Tahiri, Wassila Carpentier, Justine Gueguen, Vincent Guillemot, Céline Labeyrie, David Adams, Karine Viala, Fleur Cohen Aubart
We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83-6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software...
May 2016: Medicine (Baltimore)
Hamid Reza Saadati, Michael Wittig, Ingo Helbig, Robert Häsler, Carl A Anderson, Christopher G Mathew, Limas Kupcinskas, Miles Parkes, Tom Hemming Karlsen, Philip Rosenstiel, Stefan Schreiber, Andre Franke
BACKGROUND: Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. METHODS: One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data...
2016: BMC Medical Genetics
Jie Wang, Jonine D Figueroa, Garrick Wallstrom, Kristi Barker, Jin G Park, Gokhan Demirkan, Jolanta Lissowska, Karen S Anderson, Ji Qiu, Joshua LaBaer
BACKGROUND: Basal-like breast cancer (BLBC) is a rare aggressive subtype that is less likely to be detected through mammographic screening. Identification of circulating markers associated with BLBC could have promise in detecting and managing this deadly disease. METHODS: Using samples from the Polish Breast Cancer study, a high-quality population-based case-control study of breast cancer, we screened 10,000 antigens on protein arrays using 45 BLBC patients and 45 controls, and identified 748 promising plasma autoantibodies (AAbs) associated with BLBC...
September 2015: Cancer Epidemiology, Biomarkers & Prevention
Veronica Goitia, Marcial Oquendo, Robert Stratton
Introduction. More than 60 cases of 7p22 duplications and deletions have been reported with over 16 of them occurring without concomitant chromosomal abnormalities. Patient and Methods. We report a 29-month-old male diagnosed with autism. Whole genome chromosome SNP microarray (REVEAL) demonstrated a 1.3 Mb interstitial duplication of 7p22.1 ->p22.1 arr 7p22.1 (5,436,367-6,762,394), the second smallest interstitial 7p duplication reported to date. This interval included 14 OMIM annotated genes (FBXL18, ACTB, FSCN1, RNF216, OCM, EIF2AK1, AIMP2, PMS2, CYTH3, RAC1, DAGLB, KDELR2, GRID2IP, and ZNF12)...
2015: Case Reports in Genetics
Patrick Santens, Tim Van Damme, Wouter Steyaert, Andy Willaert, Bernard Sablonnière, Anne De Paepe, Paul J Coucke, Bart Dermaut
OBJECTIVE: To identify the genetic cause in 2 Belgian families with autosomal recessive Huntington-like disorder (HDL). METHODS: Homozygosity mapping and whole-exome sequencing in a consanguineous family as well as Sanger sequencing of the candidate gene in an independent family with HDL followed by genotype-phenotype correlation studies. RESULTS: We identified a homozygous mutation in the gene RNF216 p.(Gly456Glu) within a shared 4.8-Mb homozygous region at 7p22...
April 28, 2015: Neurology
Congfeng Xu, Kuan Feng, Xiaonan Zhao, Shiqian Huang, Yiji Cheng, Liu Qian, Yanan Wang, Hongxing Sun, Min Jin, Tsung-Hsien Chuang, Yanyun Zhang
Autophagy is an evolutionarily conserved biological process involved in an array of physiological and pathological events. Without proper control, autophagy contributes to various disorders, including cancer and autoimmune and inflammatory diseases. It is therefore of vital importance that autophagy is under careful balance. Thus, additional regulators undoubtedly deepen our understanding of the working network, and provide potential therapeutic targets for disorders. In this study, we found that RNF216 (ring finger protein 216), an E3 ubiquitin ligase, strongly inhibits autophagy in macrophages...
2014: Autophagy
Ketil Heimdal, Monica Sanchez-Guixé, Ingvild Aukrust, Jens Bollerslev, Ove Bruland, Greg Eigner Jablonski, Anne Kjersti Erichsen, Einar Gude, Jeanette A Koht, Sigrid Erdal, Torunn Fiskerstrand, Bjørn Ivar Haukanes, Helge Boman, Lise Bjørkhaug, Chantal M E Tallaksen, Per M Knappskog, Stefan Johansson
BACKGROUND: A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism. METHODS AND RESULTS: With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c...
September 26, 2014: Orphanet Journal of Rare Diseases
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