title: ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.
abstract: Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.
authors.affiliation: Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.affiliation: Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.|Center for Metabolic Diseases, University Hospital of Leuven, Leuven, Belgium.
authors.forename: Daisy
authors.initials: D
authors.lastname: Rymen
authors.affiliation: Section of Experimental Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Eklund
authors.affiliation: Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Raymond
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.affiliation: Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California.|Department of Pediatrics, University of California-Irvine School of Medicine, Orange, California.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
authors.affiliation: Division of Pediatric Neurology, Baskent University School of Medicine, Ankara, Turkey.
authors.forename: Fusun
authors.initials: F
authors.lastname: Alehan
authors.affiliation: Department of Clinical Genetics, Medical University, Bialystok, Poland.
authors.forename: Alina T
authors.initials: AT
authors.lastname: Midro
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.|Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: Pediatric Neurology Policlinico, University of Catania, Catania, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Barone
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.affiliation: Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, Iowa.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Brumbaugh
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Katie
authors.initials: K
authors.lastname: Clarkson
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: F Sessions
authors.initials: FS
authors.lastname: Cole
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Shawn
authors.initials: S
authors.lastname: O'Connor
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, University Hospital Gent, Gent, Belgium.
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.affiliation: Clinical Genetics Program, Carolinas Health Care, Levine Childrens Hospital, Charlotte, North Carolina.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Demmer
authors.affiliation: Centro de Desenvolvimento da Criança- Pediatric Hospital - CHUC, Coimbra, Portugal.
authors.forename: Luisa
authors.initials: L
authors.lastname: Diogo
authors.affiliation: Division of Pediatric Neurology, Washington University, St. Louis, Missouri.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Fay
authors.affiliation: Department of Pediatrics, Section of Metabolic Disease, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania.
authors.forename: Can
authors.initials: C
authors.lastname: Ficicioglu
authors.affiliation: Centre for Inherited Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Fiumara
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Department of Pediatrics, Section of Metabolic Disease, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ganetzky
authors.affiliation: Hunter Genetics, Waratah, New South Wales, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Goel
authors.affiliation: Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, Iowa.
authors.forename: Lyndsay A
authors.initials: LA
authors.lastname: Harshman
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Center for Metabolic Diseases, University Hospital of Leuven, Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona.
authors.forename: Philip M
authors.initials: PM
authors.lastname: James
authors.affiliation: Pediatric Neurology, Stormont-Vail Health Care, Topeka, Kansas.
authors.forename: Daniel
authors.initials: D
authors.lastname: Katz
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Keldermans
authors.affiliation: Department of Pediatrics, Odense University Hospital, Odense, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Kibaek
authors.affiliation: Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kornberg
authors.affiliation: Human Genetics and Genomic Medicine, University of Southampton and Wessex Clinical Genetics Service, Southampton, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lachlan
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: Christina
authors.initials: C
authors.lastname: Lam
authors.affiliation: Department of Metabolic Medicine, Royal Children's Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Yaplito-Lee
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Metabolic Medicine, Royal Children's Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Peters
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Race
authors.affiliation: Department of Pediatric Neurology and Metabolism, University Hospital of Brussels, Brussels, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Régal
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rush
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: S Lane
authors.initials: SL
authors.lastname: Rutledge
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Erika
authors.initials: E
authors.lastname: Souche
authors.affiliation: Carolinas Healthcare System, Charlotte, North Carolina.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Sparks
authors.affiliation: Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, Iowa.
authors.forename: Pamela
authors.initials: P
authors.lastname: Trapane
authors.affiliation: Division of Genetics and Metabolism, University of South Florida, Tampa, Florida.
authors.forename: Amarilis
authors.initials: A
authors.lastname: Sanchez-Valle
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.|Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.affiliation: Department of Pediatrics, Hospital of Ostfold N-1603 Fredrikstad, Norway.
authors.forename: Arve
authors.initials: A
authors.lastname: Vøllo
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Waechter
authors.affiliation: Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California.|Department of Pediatrics, University of California-Irvine School of Medicine, Orange, California.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wong
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina.
authors.forename: Tim
authors.initials: T
authors.lastname: Wood
authors.affiliation: Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Yang
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Hudson H
authors.initials: HH
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mesh_terms: D015415:Biomarkers / Q000378:metabolism; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005804:Genes, Lethal; D006031:Glycosylation; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics*; D009154:Mutation; D011134:Polysaccharides / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D011134:Polysaccharides; D008364:Mannosyltransferases; C035777:chitobiosyldiphosphodolichol beta-mannosyltransferase
keywords: CDG; asparagine-linked glycosylation protein 1; carbohydrate-deficient transferrin; xeno-tetrasaccharide