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Congenital disorder of glycosylation

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 cause congenital disorders in humans. Insight regarding the functional consequences of this defective glycosylation and the identity of specific glycoproteins affected are lacking. A chemical glycobiology strategy was adopted to identify surface glycoproteins most sensitive to altered glycosylation in COG-deficient CHO cells. Following metabolic labeling, an unexpected increase in GalNAz incorporation into several glycoproteins, including alpha-dystroglycan (α-DG), was noted in cog1 -deficient ldlB cells...
July 26, 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...
May 10, 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...
July 18, 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...
June 20, 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
D Marques-da-Silva, R Francisco, V Dos Reis Ferreira, L Forbat, R Lagoa, P A Videira, P Witters, J Jaeken, D Cassiman
Congenital disorders of glycosylation (CDG) are ultra-rare diseases showing a great phenotypic diversity ranging from mono- to multi-organ/multisystem involvement. Liver involvement, mostly nonprogressive, is often reported in CDG patients. The main objectives of this work were (1) to better understand liver involvement in CDG patients through a liver electronic questionnaire targeting CDG families (LeQCDG) and (2) to compare responses from LeQCDG participants with literature review regarding the prevalence of liver disease and the occurrence of liver symptoms in CDG patients...
July 15, 2018: JIMD Reports
Marco Trinchera, Rossella Parini, Rossella Indellicato, Ruben Domenighini, Fabio dall'Olio
Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distinct mutations in the B4GALNT1 gene, encoding GM2/GD2/GA2 synthase. Patients suffering from ST3GAL5 deficiency present a devastating syndrome characterized by early onset and dramatic neurological and cognitive impairment, sometimes associated with dyspigmentation and an increased blood lactate concentration...
August 2018: Molecular Genetics and Metabolism
Sandrine Duvet, Dounia Mouajjah, Romain Péanne, Gert Matthijs, Kimiyo Raymond, Jaak Jaeken, Eva Morava, François Foulquier
Congenital Disorders of Glycosylation are a very heterogeneous group of genetic protein and lipid glycosylation abnormalities. With some 33 reported patients, MAN1B1-CDG belongs to the more frequent causes of CDG-II. MAN1B1 encodes an α (1,2)-mannosidase that removes the terminal mannose residue from the middle branch. Several methods have been proposed to characterize the glycosylation changes. In MAN1B1-CDG, the abnormal accumulating N-glycan structures are mostly absent or found in trace amounts in total human serum...
June 26, 2018: Electrophoresis
Alberto Bresciani, Ottavia Cecchetti, Antonino Missineo, Pier Giorgio Pacifici, Licia Tomei, Steven Rodems
Glycosylation is a key posttranslational modification that tags protein to membranes, organelles, secretory pathways, and degradation. Aberrant protein glycosylation is present both in acquired diseases, such as cancer and neurodegeneration, and in congenital disorders of glycosylation (CDGs). Consequently, the ability to interrogate the activity of enzymes that can modify protein glycan moieties is key for drug discovery projects aimed at finding modulators of these enzymes. To date, low-throughput technologies such as SDS-PAGE and mass spectrometry have been used, which are not suitable for compound screening in drug discovery...
June 1, 2018: SLAS Discovery
Kristyna Skrenkova, Sanghyeon Lee, Katarina Lichnerova, Martina Kaniakova, Hana Hansikova, Martin Zapotocky, Young Ho Suh, Martin Horak
N -methyl-D-aspartate receptors (NMDARs) play critical roles in both excitatory neurotransmission and synaptic plasticity. NMDARs containing the nonconventional GluN3A subunit have different functional properties compared to receptors comprised of GluN1/GluN2 subunits. Previous studies showed that GluN1/GluN2 receptors are regulated by N -glycosylation; however, limited information is available regarding the role of N -glycosylation in GluN3A-containing NMDARs. Using a combination of microscopy, biochemistry, and electrophysiology in mammalian cell lines and rat hippocampal neurons, we found that two asparagine residues (N203 and N368) in the GluN1 subunit and three asparagine residues (N145, N264 and N275) in the GluN3A subunit are required for surface delivery of GluN3A-containing NMDARs...
2018: Frontiers in Molecular Neuroscience
Meena Balasubramanian, Diana S Johnson
BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases due to impaired lipid and protein glycosylation. It comprises a characteristic high frequency of intellectual disability (ID) and a wide range of clinical phenotypes. OBJECTIVE: To identify the underlying diagnosis in two families each with two siblings with variable level of ID through trio whole exome sequencing. METHODS: Both the families were recruited to the Deciphering Developmental Disorders (DDD) study to identify the aetiology for their ID...
June 14, 2018: European Journal of Medical Genetics
Kristen Westenfield, Kyriakie Sarafoglou, Laura C Speltz, Elizabeth I Pierpont, Joan Steyermark, David Nascene, Matthew Bower, Mary Ella Pierpont
BACKGROUND: Congenital disorders of glycosylation are rare conditions caused by genetic defects in glycan synthesis, processing or transport. Most congenital disorders of glycosylation involve defects in the formation or transfer of the lipid-linked oligosaccharide precursor of N-linked glycans. SLC35A2-CDG (previously CDG-IIm) is caused by hemizygous or heterozygous mutations in the X-linked gene SLC35A2 that encodes a UDP-galactose transporter. To date there have only been 10 reported patients with SLC35A2 mutations...
June 15, 2018: BMC Medical Genetics
Midori Ishii, Vladimir V Lupashin, Akihiko Nakano
The Golgi apparatus is a central station for protein trafficking in eukaryotic cells. A widely accepted model of protein transport within the Golgi apparatus is cisternal maturation. Each cisterna has specific resident proteins, which are thought to be maintained by COPI-mediated transport. However, the mechanisms underlying specific sorting of these Golgi-resident proteins remain elusive. To obtain a clue to understand the selective sorting of vesicles between the Golgi cisterenae, we investigated the molecular arrangements of the conserved oligomeric Golgi (COG) subunits in yeast cells...
July 19, 2018: Cell Structure and Function
Pedro M Rodríguez Cruz, Jacqueline Palace, David Beeson
Congenital myasthenic syndromes (CMS) are genetic disorders characterised by impaired neuromuscular transmission. This review provides an overview on CMS and highlights recent advances in the field, including novel CMS causative genes and improved therapeutic strategies. CMS due to mutations in SLC5A7 and SLC18A3 , impairing the synthesis and recycling of acetylcholine, have recently been described. In addition, a novel group of CMS due to mutations in SNAP25B , SYT2 , VAMP1 , and UNC13A1 encoding molecules implicated in synaptic vesicles exocytosis has been characterised...
June 5, 2018: International Journal of Molecular Sciences
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 nonspecific, 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
Yu Ding, Niu Li, Gouying Chang, Juan Li, Ruen Yao, Yiping Shen, Jian Wang, Xiaodong Huang, Xiumin Wang
Background The phosphoglucomutase 1 (PGM1) enzyme plays a central role in glucose homeostasis by catalyzing the inter-conversion of glucose 1-phosphate and glucose 6-phosphate. Recently, PGM1 deficiency has been recognized as a cause of the congenital disorders of glycosylation (CDGs). Methods Two Chinese Han pediatric patients with recurrent hypoglycemia, hepatopathy and growth retardation are described in this study. Targeted gene sequencing (TGS) was performed to screen for causal genetic variants in the genome of the patients and their parents to determine the genetic basis of the phenotype...
July 26, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
H A Kingma, F H van der Sluijs, M R Heiner-Fokkema
Background Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most frequently used screening method is sialotransferrin profiling using isoelectric focusing (IEF). Capillary zone electrophoresis (CZE) may be a simple and fast alternative. We investigated the Capillarys™ CDT assay (Sebia, France) to screen for N-glycosylation disorders, using IEF as gold standard. Methods Intra- and inter-assay precision were established, and analyses in heparin-anticoagulated plasma and serum were compared...
January 1, 2018: Annals of Clinical Biochemistry
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...
July 2018: Molecular Genetics and Metabolism
Katsuyuki Yokoi, Yoko Nakajima, Tamae Ohye, Hidehito Inagaki, Yoshinao Wada, Tokiko Fukuda, Hideo Sugie, Isao Yuasa, Tetsuya Ito, Hiroki Kurahashi
Phosphoglucomutase 1 (PGM1) deficiency is a recently defined disease characterized by glycogenosis and a congenital glycosylation disorder caused by recessive mutations in the PGM1 gene. We report a case of a 12-year-old boy with first-cousin parents who was diagnosed with a PGM1 deficiency due to significantly decreased PGM1 activity in his muscle. However, Sanger sequencing revealed no pathogenic mutation in the PGM1 gene in this patient. As this case presented with a cleft palate in addition to hypoglycemia and elevated transaminases and creatine kinase, karyotyping was performed and identified homozygous inv(1)(p31...
May 12, 2018: JIMD Reports
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