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Albina Nowak, Thomas P Mechtler, Robert J Desnick, David C Kasper
BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the α-galactosidase A gene (GLA) that result in absent or markedly reduce α-galactosidase A (α-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte α-GalA activities...
October 19, 2016: Molecular Genetics and Metabolism
Takashi Kodama, Takahiro Tsukimura, Ikuo Kawashima, Atsuko Sato, Hitoshi Sakuraba, Tadayasu Togawa
In Fabry disease, large amounts of globotriaosylceramide (Gb3) and related glycosphingolipids accumulate in organs due to a deficiency of α-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) with recombinant GLA is now available, and it has been reported that ERT is beneficial for patients with Fabry disease, especially those who start treatment at an early stage of the disease. However, it seems that the efficacy of ERT differs with each organ, and Gb3 accumulated in the kidneys shows resistance to ERT when it is started at a late stage...
October 12, 2016: Molecular Genetics and Metabolism
K V Firsov, A S Kotov
Fabry disease (Anderson-Fabry disease) is an X-linked recessive lysosomal storage disorder resulting from deficient activity of lysosomal hydrolase, alpha-galactosidase A (alpha-Gal A), which leads to progressive accumulation of globotriaosylceramide (Gb3) in various cells, predominantly endothelial and vascular smooth muscle cells, with clinical manifestations affecting major organs including the central nervous system. Manifestations of Fabry disease include progressive renal and cardiac insufficiency, neuropathic pain, stroke and cerebral disease, skin and gastrointestinal symptoms...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Griselda Hernández, David M LeMaster
Both (15)N chemical shift anisotropy (CSA) and sufficiently rapid exchange linebroadening transitions exhibit relaxation contributions that are proportional to the square of the magnetic field. Deconvoluting these contributions is further complicated by residue-dependent variations in protein amide (15)N CSA values which have proven difficult to accurately measure. Exploiting recently reported improvements for the implementation of T1 and T1ρ experiments, field strength-dependent studies have been carried out on the B3 domain of protein G (GB3) as well as on the immunophilin FKBP12 and a H87V variant of that protein in which the major conformational exchange linebroadening transition is suppressed...
October 12, 2016: Journal of Biomolecular NMR
H Trimarchi, R Canzonieri, A Schiel, C Costales-Collaguazo, J Politei, A Stern, M Paulero, T Rengel, J Andrews, M Forrester, M Lombi, V Pomeranz, R Iriarte, A Muryan, E Zotta, M D Sanchez-Niño, A Ortiz
BACKGROUND: Certain glomerulopathies are associated with increased levels of CD80 (B7-1). We measured the urinary excretion of CD80, podocyturia and proteinuria in controls and in subjects with Fabry disease either untreated or on enzyme replacement therapy (ERT). METHODS: Cross-sectional study including 65 individuals: controls (n = 20) and Fabry patients (n = 45, 23 of them not on ERT and 22 on ERT). Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), urinary uCD80/creatinine ratio (uCD80) and podocyturia...
October 13, 2016: Journal of Translational Medicine
Mona Abaoui, Michel Boutin, Pamela Lavoie, Christiane Auray-Blais
Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and resulting in the accumulation of glycosphingolipids in different tissues and biological fluids. Glycosphingolipid biomarkers, such as globotriaosylceramide (Gb3 ) isoforms, globotriaosylsphingosine (lyso-Gb3 ) and related analogs, and galabiosylceramide (Ga2 ) isoforms and analogs, are found to be abnormally increased in urine and in plasma of Fabry patients and have the potential to be used as specific biomarkers of the disease...
October 11, 2016: Current Protocols in Human Genetics
Ester Miranda Pereira, Anatalia Labilloy, Megan L Eshbach, Ankita Roy, Arohan R Subramanya, Semiramis Monte, Guillaume Labilloy, Ora A Weisz
BACKGROUND: Fabry Nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD) a rare X-linked lysosomal storage disorder.Gb3, the main substrate of α-gal A, progressively accumulates within cells in a variety of tissues. Establishment of cell models have been useful as a tool for testing hypotheses of disease pathogenesis. METHODS: We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type...
September 28, 2016: American Journal of Physiology. Renal Physiology
Antonio Pisani, Dario Bruzzese, Massimo Sabbatini, Letizia Spinelli, Massimo Imbriaco, Eleonora Riccio
BACKGROUND: In 2009, the agalsidase beta shortage resulted in switching to agalsidase alfa treatment for many Fabry disease patients, offering the unique opportunity to compare the effects of the two drugs. Because single studies describing effects of switching on the disease course are limited and inconclusive, we performed a systematic review and meta-analysis of existing data. METHODS: Relevant studies were identified in the PubMed, Cochrane, ISI Web, and SCOPUS databases from July 2009 to September 2015...
September 8, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Qing Shao, Carol K Hall
The adsorption of proteins on nanoparticles results in the formation of the protein corona, the composition of which determines how nanoparticles influence their biological surroundings. We seek to better understand corona formation by developing models that describe protein adsorption on nanoparticles using computer simulation results as data. Using a coarse-grained protein model, discontinuous molecular dynamics simulations are conducted to investigate the adsorption of two small proteins (Trp-cage and WW domain) on a model nanoparticle of diameter 10...
October 19, 2016: Journal of Physics. Condensed Matter: An Institute of Physics Journal
Radoslaw Kaczmarek, Katarzyna Mikolajewicz, Katarzyna Szymczak, Maria Duk, Edyta Majorczyk, Anna Krop-Watorek, Anna Buczkowska, Marcin Czerwinski
Human Gb3/CD77 synthase (α1,4-galactosyltransferase) is the only known glycosyltransferase that changes acceptor specificity because of a point mutation. The enzyme, encoded by A4GALT locus, is responsible for biosynthesis of Gal(α1-4)Gal moiety in Gb3 (CD77, P(k) antigen) and P1 glycosphingolipids. We showed before that a single nucleotide substitution c.631C > G in the open reading frame of A4GALT, resulting in replacement of glutamine with glutamic acid at position 211 (substitution p. Q211E), broadens the enzyme acceptor specificity, so it can not only attach galactose to another galactose but also to N-acetylgalactosamine...
August 18, 2016: Glycoconjugate Journal
Jarmila Lakomá, Roberto Rimondini, Antonio Ferrer Montiel, Vincenzo Donadio, Rocco Liguori, Marco Caprini
Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(-/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive...
2016: Molecular Pain
Philippe Provençal, Michel Boutin, Shaalee Dworski, Bryan Au, Jeffrey A Medin, Christiane Auray-Blais
AIM: Fabry disease is a lysosomal storage disorder leading to glycosphingolipid accumulation in different organs, tissues and biological fluids. The development of a Fabry disease gene therapy trial is underway in Canada. A tool to determine the distribution of Gb3 biomarkers in tissues of Fabry mice might be applicable to monitor the effect of gene therapy. Results & methodology: An ultra-performance LC-MS/MS (UPLC-MS/MS) method for the analysis of 22 Gb3 isoform/analogs in various Fabry mice tissues was developed and validated...
September 2016: Bioanalysis
S Kadambari, C Atkinson, S Luck, M Macartney, T Conibear, I Harrison, C Booth, M Sharland, P D Griffiths
Cytomegalovirus (CMV) is the most common congenital infection in humans and a leading cause of sensorineural hearing loss. Ganciclovir (6 mg/kg twice daily for 42 days) has been shown to reduce hearing deterioration and is used in clinical practice. Vaccines and passive administration of antibody are being evaluated in randomised controlled trials in allograft candidates, women of childbearing age and pregnant women with primary CMV infection. To help define genetic variation in each of the targets of these therapeutic interventions, we amplified and sequenced genes UL97 (site utilised for ganciclovir phosphorylation), UL55 (glycoprotein B (gB) vaccine target) and UL128, UL130 and UL131a (specific monoclonal antibody targets)...
August 2, 2016: Journal of Medical Virology
Ieva Ailte, Anne Berit Dyve Lingelem, Simona Kavaliauskiene, Jonas Bergan, Audun Sverre Kvalvaag, Anne-Grethe Myrann, Tore Skotland, Kirsten Sandvig
Shiga toxin (Stx), an AB5 toxin, binds specifically to the neutral glycosphingolipid Gb3 at the cell surface before being transported into cells. We here demonstrate that addition of conical lysophospholipids (LPLs) with large head groups inhibit Stx binding to cells whereas LPLs with small head groups do not. Lysophosphatidylinositol (LPI 18:0), the most efficient LPL with the largest head group, was selected for in-depth investigations to study how the binding of Stx is regulated. We show that the inhibition of Stx binding by LPI is reversible and possibly regulated by cholesterol since addition of methyl-β-cyclodextrin (mβCD) reversed the ability of LPI to inhibit binding...
2016: Scientific Reports
Giovana Brondani Biancini, Carlos Eduardo Jacques, Tatiane Hammerschmidt, Heryk Motta de Souza, Bruna Donida, Marion Deon, Filippo Pinto Vairo, Charles Marques Lourenço, Roberto Giugliani, Carmen Regla Vargas
Fabry disease (FD) is caused by deficient activity of the lysosomal enzyme α-galactosidase A. Its substrates, mainly globotriaosylceramide (Gb3), accumulate and seem to induce other pathophysiological findings of FD. Once enzyme replacement therapy (ERT) is not completely efficient on preventing disease progress in FD patients, elucidating the underlying mechanisms in FD pathophysiology is essential to the development of additional therapeutic strategies. We investigated 58 Fabry patients (23 male and 35 female) subdivided into two groups (at diagnosis and during long-term ERT) and compared them to healthy individuals...
October 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Hugo Abensur, Marlene Antônia Dos Reis
Every cell in the human body has globotriaosylceramide accumulation (Gb3) in Fabry disease due to the mutation in gene of the enzyme α-galactosidase A. It is a disease linked to sex. The main clinical features are: cutaneous angiokeratomas; acroparestesias and early strokes; decreased sweating and heat intolerance; ocular changes; myocardial hypertrophy, arrhythmias; gastrointestinal disorders and renal involvement. Renal involvement occurs due to Gb3 accumulation in all types of renal cells. Therefore, patients may present glomerular and tubular function disorders...
June 2016: Jornal Brasileiro de Nefrologia: ʹorgão Oficial de Sociedades Brasileira e Latino-Americana de Nefrologia
Michel Boutin, Pamela Lavoie, Mona Abaoui, Christiane Auray-Blais
Fabry disease is an X-linked lysosomal storage disorder, caused by a deficit in α-galactosidase A enzyme activity, leading to the storage of sphingolipids such as globotriaosylsphingosine (lyso-Gb3 ), globotriaosylceramide (Gb3 ), and galabiosylceramide (Ga2 ) in organs, tissues and biological fluids. A recent metabolomic study performed in plasma revealed lyso-Gb3 analogs as novel Fabry disease biomarkers. These molecules correspond to lyso-Gb3 with different chemical modifications on the sphingosine chain (-C2 H4 , -H2 , +O, +H2 O, +H2 O2, and +H2 O3 )...
2016: Current Protocols in Human Genetics
Pamela Lavoie, Michel Boutin, Mona Abaoui, Christiane Auray-Blais
Fabry disease is an X-linked lysosomal storage disorder caused by the absence or reduction of the enzyme α-galactosidase A activity. Currently, globotriaosylsphingosine (lyso-Gb3 ) and globotriaosylceramide (Gb3 ) are used as biomarkers to diagnose and monitor Fabry patients. However, recent metabolomic studies have shown that several glycosphingolipids are also elevated in biological fluids of affected patients and may be related to disease manifestations. This unit describes a multiplex methodology targeting the analysis of urinary lyso-Gb3 and seven structurally related analogs...
2016: Current Protocols in Human Genetics
Tore Skotland, Kim Ekroos, Simona Kavaliauskiene, Jonas Bergan, Dimple Kauhanen, Tuulia Lintonen, Kirsten Sandvig
In this study we used water soluble stable mass isotope precursors to measure the turnover of endogenous ceramide and glycosphingolipids (GSLs) in HEp-2 cells. Cells incubated in the presence of [(13)C-U]glucose showed rapid incorporation of hexose residues with an increased mass of 6Da into GSLs. Different turnover rates of GSL classes and their molecular species were observed. Approximately 30% of the glucosylceramide (GlcCer), 50% of the lactosylceramide (LacCer) and 50% of the globotriaosylceramide (Gb3) species showed a much slower turnover than the rest...
June 27, 2016: Journal of Molecular Biology
Malte Lenders, Julia B Hennermann, Christine Kurschat, Arndt Rolfs, Sima Canaan-Kühl, Claudia Sommer, Nurcan Üçeyler, Christoph Kampmann, Nesrin Karabul, Anne-Katrin Giese, Thomas Duning, Jörg Stypmann, Johannes Krämer, Frank Weidemann, Stefan-Martin Brand, Christoph Wanner, Eva Brand
BACKGROUND: The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines. METHODS: Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed. RESULTS: Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines...
June 29, 2016: Orphanet Journal of Rare Diseases
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