Read by QxMD icon Read

Congenital disorder of glycosylation

Jessica P Lao, Nina DiPrimio, Madeleine Prangley, Feba S Sam, Joshua D Mast, Ethan O Perlstein
Phosphomannomutase 2 Deficiency (PMM2-CDG) is the most common monogenic congenital disorder of glycosylation (CDG) affecting at least 800 patients globally. PMM2 orthologs are present in model organisms, including the budding yeast Saccharomyces cerevisiae gene SEC53. Here we describe conserved genotype-phenotype relationships across yeast and human patients between five PMM2 loss-of-function missense mutations and their orthologous SEC53 mutations. These alleles range in severity from folding defective (hypomorph) to dimerization defective (severe hypomorph) to catalytic dead (null)...
December 7, 2018: G3: Genes—Genomes—Genetics
Bobby G Ng, Jill A Rosenfeld, Lisa Emrick, Mahim Jain, Lindsay C Burrage, Brendan Lee, William J Craigen, David R Bearden, Brett H Graham, Hudson H Freeze
FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia...
November 21, 2018: American Journal of Human Genetics
Albert Kelly, Aisling O'Malley, Mohammad Redha, Gerard W O'Keeffe, Denis S Barry
Glycosylation is a major post-translational modification in which a carbohydrate known as a glycan is enzymatically attached to target proteins which regulate protein folding and stability. Glycans are strongly expressed in the developing nervous system where they play multiple roles during development. The importance of these glycan epitopes in neural development is highlighted by a group of conditions known as congenital disorders of glycosylation which lead to psychomotor difficulties, mental retardation, lissencephaly, microencephaly and epilepsy...
November 25, 2018: Journal of Anatomy
R Francisco, D Marques-da-Silva, S Brasil, C Pascoal, V Dos Reis Ferreira, E Morava, J Jaeken
Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases that currently includes some 130 different types. CDG diagnosis is a challenge, not only because of this large number but also because of the huge clinical heterogeneity even within a number of CDG. In addition, the classical screening test, serum transferrin isoelectrofocusing, is only positive in about 60% of CDG, and can even become negative in some CDG particularly in PMM2-CDG, the most frequent N-glycosylation defect...
November 9, 2018: Molecular Genetics and Metabolism
Pengzhi Hu, Lamei Yuan, Hao Deng
Protein O-mannosyltransferase 1 (POMT1) is a critical enzyme participating in the first step of protein O-mannosylation. Mutations in the coding gene, POMT1, have been described to be related to a series of autosomal recessive disorders associated with defective alpha-dystroglycan glycosylation, later termed muscular dystrophy-dystroglycanopathies (MDDGs). MDDGs are characterized by a broad phenotypic spectrum of congenital muscular dystrophy or later-onset limb-girdle muscular dystrophy, accompanied by variable degrees of intellectual disability, brain defects, and ocular abnormalities...
October 2018: Mutation Research
Nanako Kanaki, Ayako Matsuda, Katsufumi Dejima, Daisuke Murata, Kazuko H Nomura, Takashi Ohkura, Keiko-Gengyo Ando, Sawako Yoshina, Shohei Mitani, Kazuya Nomura
N-linked glycosylation of proteins is the most common post-translational modification of proteins. The enzyme UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) catalyses the first step of N-glycosylation, and DPAGT1 knockout is embryonic lethal in mice. In this study, we identified the sole orthologue (algn-7) of the human DPAGT1 in the nematode C. elegans. The gene activity was disrupted by RNAi and deletion mutagenesis, which resulted in larval lethality, defects in oogenesis and oocyte-to-embryo transition...
November 16, 2018: Glycobiology
Mariska Davids, Megan S Kane, Lynne A Wolfe, Camilo Toro, Cynthia J Tifft, David Adams, Xueli Li, Mohd A Raihan, Miao He, William A Gahl, Cornelius F Boerkoel, May Christine V Malicdan
The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) studies rare genetic disorders not only to achieve diagnoses, but to understand human biology. To ascertain the contribution of protein glycosylation to rare diseases, the NIH UDP used mass spectrometry to agnostically identify abnormalities of N-linked and O-linked glycans in plasma and free oligosaccharides in the urine of 207 patients. 60% of UDP patients had a glycome profile that deviated from control values in at least 1 fluid...
October 23, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Carla Gabriela Asteggiano, Magali Papazoglu, María Beatriz Bistué Millón, María Fernanda Peralta, Nydia Beatriz Azar, Norma Spécola Spécola, Norberto Guelbert, Niels Suldrup Suldrup, Marcela Pereyra, Raquel Dodelson de Kremer
BACKGROUND: Congenital Disorders of Glycosylation (CDG) are genetic diseases caused by hypoglycosylation of glycoproteins and glycolipids. Most CDG are multisystem disorders with mild to severe involvement. METHODS: We studied 554 patients (2007-2017) with a clinical phenotype compatible with a CDG. Screening was performed by serum transferrin isoelectric focusing. The diagnosis was confirmed by genetic testing (Sanger or exome sequencing). RESULTS: A confirmed abnormal pattern was found in nine patients...
October 18, 2018: Pediatric Research
Giovanna Lucrecia Gallo, Ayelen Valko, Sofía Ivana Aramburu, Emiliana Etchegaray, Christof Völker, Armando Parodi, Cecilia D'Alessio
Glucosidase I (GI) removes the outermost glucose from protein-linked Glc3 Man9 GlcNAc2 (G3M9) in the endoplasmic reticulum (ER). Individuals with congenital disorders of glycosylation MOGS-CDG bear mutations in the GI encoding-gene ( gls1 ). Although GI absence has been reported to produce lethality in Schizosaccharomyces pombe yeasts, here we obtained two viable Δgls1 mutants, one with a very sick but not lethal phenotype ( Δgls1-S ) and the other with a healthier one ( Δgls1-H ). The sick strain displayed only G3M9 as an ER protein-linked oligosaccharide, whereas the healthier strain had both G3M9 and Man9 GlcNAc2 The lipid-linked oligosaccharide patterns of the two strains revealed that the most abundantly formed glycans were G3M9 in Δgls1-S and Glc2 Man9 GlcNAc2 in Δgls1-H , suggesting reduced alg10p glucosyltransferase activity in the Δgls1-H strain...
November 2, 2018: Journal of Biological Chemistry
Yin Yao Dong, Hua Wang, Ashley C W Pike, Stephen A Cochrane, Sadra Hamedzadeh, Filip J Wyszyński, Simon R Bushell, Sylvain F Royer, David A Widdick, Andaleeb Sajid, Helena I Boshoff, Yumi Park, Ricardo Lucas, Wei-Min Liu, Seung Seo Lee, Takuya Machida, Leanne Minall, Shahid Mehmood, Katsiaryna Belaya, Wei-Wei Liu, Amy Chu, Leela Shrestha, Shubhashish M M Mukhopadhyay, Claire Strain-Damerell, Rod Chalk, Nicola A Burgess-Brown, Mervyn J Bibb, Clifton E Barry Iii, Carol V Robinson, David Beeson, Benjamin G Davis, Elisabeth P Carpenter
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins...
November 1, 2018: Cell
Wujood Khayat, Anna Hackett, Marie Shaw, Alina Ilie, Tracy Dudding-Byth, Vera M Kalscheuer, Louise Christie, Mark A Corbett, Jane Juusola, Kathryn L Friend, Brian M Kirmse, Jozef Gecz, Michael Field, John Orlowski
We report two unrelated families with multigenerational nonsyndromic intellectual disability segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles...
October 17, 2018: Human Molecular Genetics
Anna Frappaolo, Stefano Sechi, Tadahiro Kumagai, Angela Karimpour-Ghahnavieh, Michael Tiemeyer, Maria Grazia Giansanti
Protein glycosylation, the enzymatic addition of N-linked or O-linked glycans to proteins, serves crucial functions in animal cells and requires the action of glycosyltransferases, glycosidases and nucleotide-sugar transporters, localized in the endoplasmic reticulum and Golgi apparatus. Congenital Disorders of Glycosylation (CDGs) comprise a family of multisystemic diseases caused by mutations in genes encoding proteins involved in glycosylation pathways. CDGs are classified into two large groups. Type I CDGs affect the synthesis of the dolichol-linked Glc3 Man9 GlcNac2 precursor of N-linked glycosylation or its transfer to acceptor proteins...
2018: Frontiers in Genetics
Daniel Medina-Cano, Ekin Ucuncu, Lam Son Nguyen, Michael Nicouleau, Joanna Lipecka, Jean-Charles Bizot, Christian Thiel, François Foulquier, Nathalie Lefort, Catherine Faivre-Sarrailh, Laurence Colleaux, Ida Chiara Guerrera, Vincent Cantagrel
Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3 , a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis...
October 12, 2018: ELife
Marine Houdou, Elodie Lebredonchel, Anne Garat, Sandrine Duvet, Dominique Legrand, Valérie Decool, André Klein, Mohamed Ouzzine, Bruno Gasnier, Sven Potelle, François Foulquier
Congenital disorders of glycosylation are severe inherited diseases in which aberrant protein glycosylation is a hallmark. Transmembrane protein 165 (TMEM165) is a novel Golgi transmembrane protein involved in type II congenital disorders of glycosylation. Although its biologic function is still a controversial issue, we have demonstrated that the Golgi glycosylation defect due to TMEM165 deficiency resulted from a Golgi Mn2+ homeostasis defect. The goal of this study was to delineate the cellular pathway by which extracellular Mn2+ rescues N-glycosylation in TMEM165 knockout (KO) cells...
October 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Peter Witters, Tomas Honzik, Eric Bauchart, Ruqaiah Altassan, Tiffany Pascreau, Arnaud Bruneel, Sandrine Vuillaumier, Nathalie Seta, Delphine Borgel, Gert Matthijs, Jaak Jaeken, Wouter Meersseman, David Cassiman, Lonlay Pascale de, Eva Morava
PURPOSE: PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. METHODS: We performed data analysis on PMM2-CDG patients' clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. RESULTS: On a group level, there was no significant evolution in overall clinical severity...
October 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Mattia Gentile, Emanuele Agolini, Dario Cocciadiferro, Romina Ficarella, Emanuela Ponzi, Emanuele Bellacchio, Maria F Antonucci, Antonio Novelli
Biallelic exostosin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently, it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here, we report the third family affected by AREXT2 syndrome, harboring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families...
October 4, 2018: Clinical Genetics
Thi Tuyet Mai Nguyen, Yoshiko Murakami, Kristen M Wigby, Nissan V Baratang, Justine Rousseau, Anik St-Denis, Jill A Rosenfeld, Stephanie C Laniewski, Julie Jones, Alejandro D Iglesias, Marilyn C Jones, Diane Masser-Frye, Angela E Scheuerle, Denise L Perry, Ryan J Taft, Françoise Le Deist, Miles Thompson, Taroh Kinoshita, Philippe M Campeau
Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations...
October 4, 2018: American Journal of Human Genetics
Aaron Seo, Suleyman Gulsuner, Sarah Pierce, Miri Ben-Harosh, Hanna Shalev, Tom Walsh, Tanya Krasnov, Orly Dgany, Sergei Doulatov, Hannah Tamary, Akiko Shimamura, Mary-Claire King
Severe thrombocytopenia, characterized by dysplastic megakaryocytes and intracranial bleeding, was diagnosed in six individuals from a consanguineous kindred. Three of the individuals were successfully treated by bone marrow transplant. Whole exome sequencing and homozygosity mapping of multiple family members, coupled with whole genome sequencing to reveal shared non-coding variants, revealed one potentially functional variant segregating with thrombocytopenia under a recessive model: GALE p.R51W (c.C151T, NM_001127621)...
September 20, 2018: Human Molecular Genetics
Yuko Tashima, Tetsuya Okajima
The Notch signaling pathway is highly conserved and essential for animal development. It is required for cell differentiation, survival, and proliferation. Regulation of Notch signaling is a crucial process for human health. Ligands initiate a signal cascade by binding to Notch receptors expressed on a neighboring cell. Notch receptors interact with ligands through their epidermal growth factor-like repeats (EGF repeats). Most EGF repeats are modified by O -glycosylation with residues such as O -linked N -acetylglucosamine ( O -GlcNAc), O -fucose, and O -glucose...
August 2018: Nagoya Journal of Medical Science
T Michael Yates, Mohnish Suri, Archana Desurkar, Gaetan Lesca, Carina Wallgren-Pettersson, Trine B Hammer, Ashok Raghavan, Anne-Lise Poulat, Rikke S Møller, Ann-Charlotte Thuresson, Meena Balasubramanian
We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2...
August 27, 2018: European Journal of Paediatric Neurology: EJPN
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"