title: MAN1B1 deficiency: an unexpected CDG-II.
abstract: Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium ; Center for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Daisy
authors.initials: D
authors.lastname: Rymen
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Romain
authors.initials: R
authors.lastname: Peanne
authors.affiliation: Centro de Estudio Metabalopatías Congénitas, Faculdad de Ciencias Médicas, Universidad Nacional de Córdoba, Hospital de Niños de la Santísima Trinidad, Córdoba, Argentina.
authors.forename: María B
authors.initials: MB
authors.lastname: Millón
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Race
authors.affiliation: Institute of Chemistry and Technology of Polymers, CNR, Catania, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Sturiale
authors.affiliation: Institute of Chemistry and Technology of Polymers, CNR, Catania, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Garozzo
authors.affiliation: Clinical & Molecular Genetics Unit, Institute of Child Health, University College and Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
authors.forename: Philippa
authors.initials: P
authors.lastname: Mills
authors.affiliation: Clinical & Molecular Genetics Unit, Institute of Child Health, University College and Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Clayton
authors.affiliation: Centro de Estudio Metabalopatías Congénitas, Faculdad de Ciencias Médicas, Universidad Nacional de Córdoba, Hospital de Niños de la Santísima Trinidad, Córdoba, Argentina.
authors.forename: Carla G
authors.initials: CG
authors.lastname: Asteggiano
authors.affiliation: Unidade de Genética Médica, Departamento de Genética Humana, Centro de Genética Médica - Dr. Jacinto Magalhães - INSA, IP. Porto, Portugal.
authors.forename: Dulce
authors.initials: D
authors.lastname: Quelhas
authors.affiliation: Gazi University Faculty of Medicine, Department of Paediatric Neurology, Besevler/Ankara, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Cansu
authors.affiliation: Unidade de Doenças Metabólicas, Hospital de Crianças Maria Pia, Porto, Portugal.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Martins
authors.affiliation: Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Nassogne
authors.affiliation: Unidade de Genética Médica, Departamento de Genética Humana, Centro de Genética Médica - Dr. Jacinto Magalhães - INSA, IP. Porto, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gonçalves-Rocha
authors.affiliation: Department of Child Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.affiliation: Center for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Structural and Functional Glycobiology Unit, UMR CNRS/USTL 8576, IFR 147, University of Lille 1, Villeneuve d'Ascq, France.
authors.forename: François
authors.initials: F
authors.lastname: Foulquier
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006031:Glycosylation; D006056:Golgi Apparatus / Q000235:genetics* / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008361:Mannosidases / Q000172:deficiency / Q000235:genetics*; D009154:Mutation
chemical_list: D008361:Mannosidases; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase