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Congenital disorder of glycosylation

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 Fatima Antonucci, Antonio Novelli
Biallelic Exostin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly (SSM) 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, harbouring 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
Majid Alfadhel, Amir Babiker
Inborn errors of metabolism (IEM) are heterogeneous group of disorders that might present in the clinics or emergency departments in different phenotypes, and one of these is a diabetes scenario. Diabetes is the most common endocrine disorder among children. The mechanism of how IEM could lead to diabetes is unclear; however, the postulated pathogenesis consists of three mechanisms: 1) accumulation of toxic substance in the gland, ruining structure and normal functionality, 2) disturbing energy availability required for hormone synthesis and 3) defect of complex molecules...
2018: Sudanese Journal of Paediatrics
S Fecarotta, V Gragnaniello, R Della Casa, A Romano, E Raiano, A Torella, M Savarese, V Nigro, P Strisciuglio, G Andria, G Parenti
Alpha-dystroglycanopathies are a group of progressive and untreatable neuromuscular disorders, due to aberrant alpha-dystroglycan glycosylation. We describe the effects of a short-term cycle of corticosteroid therapy in a 9-year-old boy, affected by an alpha-dystroglycanopathy due to GMPPB gene mutations. The patient was affected by a congenital progressive muscular dystrophy since the first month of life, associated with psychomotor delay, seizures, and congenital bilateral cataracts. Despite physical therapy he had a progressive motor impairment...
July 19, 2018: Neuromuscular Disorders: NMD
Kyle M Stiers, Lesa J Beamer
Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, catalyzing the conversion of glucose 1-phosphate and glucose 6-phosphate. Recently, missense variants of this enzyme were identified as causing an inborn error of metabolism, PGM1 deficiency, with features of a glycogen storage disease and a congenital disorder of glycosylation. Previous studies of selected PGM1 variants have revealed various mechanisms for enzyme dysfunction, including regions of structural disorder and side-chain rearrangements within the active site...
October 2, 2018: Structure
Bobby G Ng, Hunter R Underhill, Lars Palm, Per Bengtson, Jean-Michel Rozet, Sylvie Gerber, Arnold Munnich, Xavier Zanlonghi, Cathy A Stevens, Martin Kircher, Deborah A Nickerson, Kati J Buckingham, Kevin D Josephson, Jay Shendure, Michael J Bamshad, Hudson H Freeze, Erik A Eklund
Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death...
August 17, 2018: JIMD Reports
Emanuela Manea
Glycosylphosphatidylinositol anchored proteins (GPI-APs) represent a class of soluble proteins attached to the external leaflet of the plasma membrane by a post-translation modification, the GPI anchor. The 28 genes currently involved in the synthesis and remodelling of the GPI anchor add to the ever-growing class of congenital glycosylation disorders. Recent advances in next generation sequencing technology have led to the discovery of Mabry disease and CHIME syndrome genetic aetiology. Moreover, with each described mutation known phenotypes expand and new ones emerge without clear genotype-phenotype correlation...
September 2018: Molecular Genetics and Metabolism Reports
Seok-Ho Yu, Peng Zhao, Pradeep K Prabhakar, Tiantian Sun, Aaron Beedle, Geert-Jan Boons, Kelley W Moremen, Lance Wells, Richard Steet
Deficiency in subunits of the conserved oligomeric Golgi (COG) complex results in pleiotropic defects in glycosylation and causes congenital disorders in humans. Insight regarding the functional consequences of this defective glycosylation and the identity of specific glycoproteins affected is lacking. A chemical glycobiology strategy was adopted to identify the surface glycoproteins most sensitive to altered glycosylation in COG-deficient Chinese hamster ovary (CHO) cells. Following metabolic labeling, an unexpected increase in GalNAz incorporation into several glycoproteins, including α-dystroglycan (α-DG), was noted in cog1 -deficient ldlB cells...
September 14, 2018: Journal of Biological Chemistry
Nurulamin Abu Bakar, Nicol C Voermans, Thorsten Marquardt, Christian Thiel, Mirian C H Janssen, Hana Hansikova, Ellen Crushell, Jolanta Sykut-Cegielska, Francis Bowling, Lars MØrkrid, John Vissing, Eva Morava, Monique van Scherpenzeel, Dirk J Lefeber
Phosphoglucomutase 1 (PGM1) deficiency results in a mixed phenotype of a Glycogen Storage Disorder and a Congenital Disorder of Glycosylation (CDG). Screening for abnormal glycosylation has identified more than 40 patients, manifesting with a broad clinical and biochemical spectrum which complicates diagnosis. Together with the availability of D-galactose as dietary therapy, there is an urgent need for specific glycomarkers for early diagnosis and treatment monitoring. We performed glycomics profiling by high-resolution QTOF mass spectrometry in a series of 19 PGM1-CDG patients, covering a broad range of biochemical and clinical severity...
September 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Arif O Khan
PURPOSE: Early-onset retinal dystrophy is usually isolated but can also be the presenting manifestation of an undiagnosed systemic disease. The purpose of this report is to highlight the initial presentation of a girl with early-onset retinal dystrophy and chronic dermatitis who was found to have an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG). METHODS: Retrospective case report. RESULTS: A 13-year-old Baluchi girl was referred for evaluation of low vision since soon after birth...
October 2018: Ophthalmic Genetics
Ann-Kathrin Zaum, Konstantinos Kolokotronis, Wolfram Kress, Hans-Hilmar Goebel, Simone Rost, Jürgen Seeger
Dystroglycanopathies are a diverse group of neuromuscular disorders caused by aberrant glycosylation of alpha-dystroglycan. TMEM5 is one of many glycosyltransferases recently described to be associated with alpha-dystroglycanopathies. We report the case of a 15-year-old boy suffering from a congenital muscular dystrophy with elevated serum creatine kinase levels and an almost complete absence of alpha-dystroglycan in muscle biopsy. The clinical course was milder than any previously reported case and did not include brain or eye defects...
August 2018: Neuromuscular Disorders: NMD
Jee-San Lee, Mi-Yeun Kim, Eun-Ran Park, Yan Nan Shen, Ju-Yeon Jeon, Eung-Ho Cho, Sun-Hoo Park, Chul Ju Han, Dong Wook Choi, Ja June Jang, Kyung-Suk Suh, Jungil Hong, Sang Bum Kim, Kee-Ho Lee
Transmembrane protein 165 (TMEM165), a Golgi protein, functions in ion homeostasis and vesicular trafficking in the Golgi apparatus. While mutations in TMEM165 are known to cause human 'congenital disorders of glycosylation', a recessive autosomal metabolic disease, the potential association of this protein with human cancer development has not been explored to date. In the present study, we revealed that TMEM165 is overexpressed in HCC and its depletion weakens the invasive activity of cancer cells through suppression of matrix metalloproteinase‑2 (MMP‑2) expression...
September 2018: Oncology Reports
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