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Arnaud Bruneel, Sophie Cholet, Valérie Drouin-Garraud, Marie-Line Jacquemont, Aline Cano, André Mégarbané, Coralie Ruel, David Cheillan, Thierry Dupré, Sandrine Vuillaumier-Barrot, Nathalie Seta, François Fenaille
Congenital disorders of glycosylation (CDG) are rare autosomal genetic diseases affecting the glycosylation of proteins and lipids. Since CDG-related clinical symptoms are classically extremely variable and non-specific, a combination of electrophoretic, mass spectrometric and gene sequencing techniques is often mandatory for obtaining a definitive CDG diagnosis, as well as identifying causative gene mutations and deciphering the underlying biochemical mechanisms. Here, we illustrate the potential of integrating data from capillary electrophoresis of transferrin, two-dimensional electrophoresis of N- and O-glycoproteins, mass spectrometry analyses of total serum N-linked glycans and mucin core1 O-glycosylated apolipoprotein C-III for the determination of various culprit CDG gene mutations...
June 5, 2018: Electrophoresis
Muriel Girard, Aurélia Poujois, Monique Fabre, Florence Lacaille, Dominique Debray, Marlène Rio, François Fenaille, Sophie Cholet, Coralie Ruel, Elizabeth Caussé, Janick Selves, Laure Bridoux-Henno, France Woimant, Thierry Dupré, Sandrine Vuillaumier-Barrot, Nathalie Seta, Laurent Alric, Pascale de Lonlay, Arnaud Bruneel
Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement...
May 9, 2018: Molecular Genetics and Metabolism
Pingping Zhang, Xin Wang, Zhijie Gao, Xiaoyan Liu, Qian Chen
OBJECTIVE To identify potential mutation in a patient with cutis laxa through exome sequencing of genetic disease-related genes and explore its clinical and genetic features. METHODS Clinical data was collected for the proband and her parents. Exome sequencing was carried out on the proband. Suspected mutations were verified by Sanger sequencing. RESULTS Exome sequencing identified a compound heterozygous mutation of the ATP6V0A2 gene, c.187C>T (p.R63X) and c.1189G>C (p.A397P), in the proband. The mutations were respectively inherited from the father and mother...
February 10, 2018: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Sally Esmail, Norbert Kartner, Yeqi Yao, Joo Wan Kim, Reinhart A F Reithmeier, Morris F Manolson
The a subunit is the largest of 15 different subunits that make up the vacuolar H+ -ATPase (V-ATPase) complex, where it functions in proton translocation. In mammals, this subunit has four paralogous isoforms, a 1- a 4, which may encode signals for targeting assembled V-ATPases to specific intracellular locations. Despite the functional importance of the a subunit, its structure remains controversial. By studying molecular mechanisms of human disease-causing missense mutations within a subunit isoforms, we may identify domains critical for V-ATPase targeting, activity and/or regulation...
February 23, 2018: Journal of Biological Chemistry
José D A Araújo, Andrea Ghelfi, Adalberto L Val
The Amazon basin includes 1000s of bodies of water, that are sorted according to their color in three types: blackwater, clearwater, and whitewater, which significantly differ in terms of their physicochemical parameters. More than 3,000 species of fish live in the rivers of the Amazon, among them, the sardine, Triportheus albus, which is one of the few species that inhabit all three types of water. The purpose of our study was to analyze if the gene expression of T. albus is determined by the different types of water, that is, if the species presents phenotypic plasticity to live in blackwater, clearwater, and whitewater...
2017: Frontiers in Genetics
Celia Pérez-Cerdá, Ma Luisa Girós, Mercedes Serrano, M Jesús Ecay, Laura Gort, Belén Pérez Dueñas, Celia Medrano, Alfredo García-Alix, Rafael Artuch, Paz Briones, Belén Pérez
OBJECTIVE: To describe the clinical, biochemical, and genetic features of patients with congenital disorders of glycosylation (CDG) identified in Spain during the last 20 years. STUDY DESIGN: Patients were selected among those presenting with multisystem disease of unknown etiology. The isoforms of transferrin and of ApoC3 and dolichols were analyzed in serum; phosphomannomutase and mannosephosphate isomerase activities were measured in fibroblasts. Conventional or massive parallel sequencing (customized panel or Illumina Clinical-Exome Sequencing TruSight One Gene Panel) was used to identify genes and mutations...
April 2017: Journal of Pediatrics
Amal Al Teneiji, Theodora U J Bruun, Sarah Sidky, Dawn Cordeiro, Ronald D Cohn, Roberto Mendoza-Londono, Mahendranath Moharir, Julian Raiman, Komudi Siriwardena, Lianna Kyriakopoulou, Saadet Mercimek-Mahmutoglu
BACKGROUND: Congenital disorders of glycosylation (CDG) are inborn defects of glycan metabolism. They are multisystem disorders. Analysis of transferrin isoforms is applied as a screening test for CDG type I (CDG-I) and type II (CDG-II). We performed a retrospective cohort study to determine spectrum of phenotype and genotype and prevalence of the different subtypes of CDG-I and CDG-II. MATERIAL AND METHODS: All patients with CDG-I and CDG-II evaluated in our institution's Metabolic Genetics Clinics were included...
March 2017: Molecular Genetics and Metabolism
Madhulika Tripathi, Cheng Wu Zhang, Brijesh Kumar Singh, Rohit Anthony Sinha, Kyaw Thu Moe, Deidre Anne DeSilva, Paul Michael Yen
Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect...
December 8, 2016: Cell Death & Disease
Rony Cohen, Ayelet Halevy, Sharon Aharoni, Dror Kraus, Osnat Konen, Lina Basel-Vanagaite, Hadassa Goldberg-Stern, Rachel Straussberg
Cutis laxa syndromes are rare inherited disorders of skin and connective tissue metabolism associated with variable systemic involvement. The main clinical manifestation is loose, wrinkled, redundant, inelastic skin, hypotonia, typical facies including short nose and down-slanting palpebral fissures, and varying degrees of developmental delay. The aim of this report is to describe two siblings diagnosed with a moderate form of ATP6V0A2-related cutis laxa with polymicrogyria (cobblestone-like brain dysgenesis)...
October 2016: Neurogenetics
Miyako Udono, Kaoru Fujii, Gakuro Harada, Yumi Tsuzuki, Keishi Kadooka, Pingbo Zhang, Hiroshi Fujii, Maho Amano, Shin-Ichiro Nishimura, Kosuke Tashiro, Satoru Kuhara, Yoshinori Katakura
Many genes and signaling pathways have been found to be involved in cellular senescence program. In the present study, we have identified 16 senescence-associated genes by differential proteomic analysis of the normal human diploid fibroblast cell line, TIG-1, and focused on ATP6V0A2. The aim of this study is to clarify the role of ATP6V0A2, the causal gene for ARCL2, a syndrome of abnormal glycosylation and impaired Golgi trafficking, in cellular senescence program. Here we showed that ATP6V0A2 is critical for cellular senescence; impaired expression of ATP6V0A2 disperses the Golgi structure and triggers senescence, suggesting that ATP6V0A2 mediates these processes...
2015: Scientific Reports
Mukesh K Jaiswal, Varkha Agrawal, Gajendra K Katara, Sahithi Pamarthy, Arpita Kulshrestha, Gerard Chaouat, Alice Gilman-Sachs, Kenneth D Beaman
The a2 isoform of vacuolar-ATPase (ATP6V0A2, referred to as a2V) is required for normal spermatogenesis and maturation of sperm. Treatment of male mice with anti-a2V disturbs the testicular cytokine/chemokine balance and leads to severe deficiencies of spermatogenesis. The aim of the present study was to investigate the role of a2V in male fertility and in the regulation of apoptotic pathways required for normal spermatogenesis in mice. To study the role of a2V single dose of anti-a2V monoclonal antibody or mouse IgG isotype (3μg/animal) was injected i...
November 2015: Journal of Reproductive Immunology
Andrea Di Cristofori, Stefano Ferrero, Irene Bertolini, Gabriella Gaudioso, Maria Veronica Russo, Valeria Berno, Marco Vanini, Marco Locatelli, Mario Zavanone, Paolo Rampini, Thomas Vaccari, Manuela Caroli, Valentina Vaira
The vacuolar H+ ATPase (V-ATPase) is a proton pump responsible for acidification of cellular microenvironments, an activity exploited by tumors to survive, proliferate and resist to therapy. Despite few observations, the role of V-ATPase in human tumorigenesis remains unclear.We investigated the expression of ATP6V0C, ATP6V0A2, encoding two subunits belonging to the V-ATPase V0 sector and ATP6V1C, ATP6V1G1, ATPT6V1G2, ATP6V1G3, which are part of the V1 sector, in series of adult gliomas and in cancer stem cell-enriched neurospheres isolated from glioblastoma (GBM) patients...
July 10, 2015: Oncotarget
Stéphanie Yen-Nicolaÿ, Céline Boursier, Marlène Rio, Dirk J Lefeber, Antoine Pilon, Nathalie Seta, Arnaud Bruneel
PURPOSE: The O-glycan abnormalities accompanying some congenital disorders of glycosylation, namely conserved oligomeric Golgi-congenital disorders of glycosylation (COG-CDGs) and ATP6V0A2-CDGs, are mainly detected using electrophoresis methods applied to circulating apolipoprotein C-III. The objective of this study was to evaluate the reliability of MALDI-TOF MS of apoC-III for the detection and characterization of CDG-associated O-glycan defects. EXPERIMENTAL DESIGN: plasmas from CDG-negative, COG-CDG, and ATP6V0A2-CDG patients were analyzed and results were compared to those obtained using 2DE followed by Western blot...
August 2015: Proteomics. Clinical Applications
Hyeon-Min Jang, Gisela F Erf, Kaylee C Rowland, Byung-Whi Kong
BACKGROUND: The Smyth line (SL) chicken is the only animal model for autoimmune vitiligo that spontaneously displays all clinical and biological manifestations of the human disorder. To understand the genetic components underlying the susceptibility to develop SL vitiligo (SLV), whole genome resequencing analysis was performed in SLV chickens compared with non-vitiliginous parental Brown line (BL) chickens, which maintain a very low incidence rate of vitiligo. RESULTS: Illumina sequencing technology and reference based assembly on Red Jungle Fowl genome sequences were used...
2014: BMC Genomics
Dorus Kouwenberg, Thatjana Gardeitchik, Miski Mohamed, Dirk J Lefeber, Eva Morava
Glycosylation is the posttranslational coupling of sugar chains to proteins or lipids. Proper glycosylation is essential for normal protein structure, function, and trafficking. Mutations in the glycosylation pathway lead to a phenotypically heterogeneous group of metabolic disorders, the congenital disorders of glycosylation (CDG). Some of these conditions, including PMM2-CDG, frequently present with recognizable skin abnormalities such as abnormal fat distribution, skin wrinkling, or peau d'orange, whereas others, such as COG7-CDG and ATP6V0A2-CDG, have been described in association with cutis laxa: wrinkled, inelastic, and sagging skin...
January 2014: Pediatric Dermatology
Marie T Greally, Neale N Kalis, Wahid Agab, Kasim Ardati, Sanda Giurgea, Uwe Kornak, Lionel Van Maldergem
Through a survey of more than 20 patients with a specific subgroup of autosomal recessive congenital cutis laxa (ARCL), namely ATP6V0A2-related cutis laxa, we noted that the clinical findings on three patients included pretibial pseudo-ecchymotic skin lesions very similar to those found in classical Ehlers-Danlos syndrome. The finding is apparently age-related, occurring during the second decade in two of the three patients.
May 2014: American Journal of Medical Genetics. Part A
Thatjana Gardeitchik, Miski Mohamed, Björn Fischer, Martin Lammens, Dirk Lefeber, Baiba Lace, Michael Parker, Ki-Joong Kim, Bing C Lim, Johannes Häberle, Livia Garavelli, Sujatha Jagadeesh, Ariana Kariminejad, Deanna Guerra, Michel Leão, Riikka Keski-Filppula, Han Brunner, Leo Nijtmans, Bert van den Heuvel, Ron Wevers, Uwe Kornak, Eva Morava
Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL...
July 2014: European Journal of Human Genetics: EJHG
Kuniaki Ota, Mukesh Kumar Jaiswal, Sivakumar Ramu, Rajasinjham Jeyendran, Joanne Kwak-Kim, Alice Gilman-Sachs, Kenneth D Beaman
BACKGROUND: A number of laboratory tests have been developed to determine properties of spermatozoa quality but few have been adopted into routine clinical use in place of the WHO semen analysis. We investigated whether Atp6v0a2 (a2 isoform of vacuolar ATPase) is associated with abnormal semen quality and changes in chemokine-cytokine profiles in infertile men. PATIENTS AND METHODS: Semen samples were collected from 35 healthy donors and 35 infertile men at the Andrology laboratory from August 2011 to June 2012...
2013: PloS One
R Zeevaert, F de Zegher, L Sturiale, D Garozzo, M Smet, M Moens, G Matthijs, J Jaeken
Three patients belonging to two families presented with a psychomotor-dysmorphism syndrome including postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Other features were muscular hypotrophy, fat excess, partial growth hormone deficiency, and, in two of the three patients, episodes of unexplained fever. Additional investigations showed mild to moderate increases of serum transaminases (particularly of aspartate transaminase (AST)), creatine kinase (CK), and lactate dehydrogenase (LDH), as well as decreased coagulation factors VIII, IX, XI, and protein C...
2013: JIMD Reports
Björn Fischer, Aikaterini Dimopoulou, Johannes Egerer, Thatjana Gardeitchik, Alexa Kidd, Dominik Jost, Hülya Kayserili, Yasemin Alanay, Iliana Tantcheva-Poor, Elisabeth Mangold, Cornelia Daumer-Haas, Shubha Phadke, Reto I Peirano, Julia Heusel, Charu Desphande, Neerja Gupta, Arti Nanda, Emma Felix, Elisabeth Berry-Kravis, Madhulika Kabra, Ron A Wevers, Lionel van Maldergem, Stefan Mundlos, Eva Morava, Uwe Kornak
Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H(+)-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications...
November 2012: Human Genetics
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