Journal article
ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients
Human mutation, Vol.37(7), pp.653-660
07/2016
DOI: 10.1002/humu.22983
PMCID: PMC4907823
PMID: 26931382
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.
Details
- Title: Subtitle
- ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients
- Creators
- Bobby G Ng - Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CaliforniaSergey A Shiryaev - Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CaliforniaDaisy Rymen - Center for Metabolic Diseases, University Hospital of Leuven, Leuven, BelgiumErik A Eklund - Section of Experimental Pediatrics, Department of Clinical Sciences, Lund University, Lund, SwedenKimiyo Raymond - Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MinnesotaMartin Kircher - Department of Genome Sciences, University of Washington, Seattle, WashingtonJose E Abdenur - Department of Pediatrics, University of California-Irvine School of Medicine, Orange, CaliforniaFusun Alehan - Division of Pediatric Neurology, Baskent University School of Medicine, Ankara, TurkeyAlina T Midro - Department of Clinical Genetics, Medical University, Bialystok, PolandMichael J Bamshad - Department of Pediatrics, University of Washington, Seattle, WashingtonRita Barone - Pediatric Neurology Policlinico, University of Catania, Catania, ItalyGerard T Berry - Department of Pediatrics, Harvard Medical School, Boston, MassachusettsJane E Brumbaugh - Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, IowaKati J Buckingham - Department of Pediatrics, University of Washington, Seattle, WashingtonKatie Clarkson - Greenwood Genetic Center, Greenwood, South CarolinaF Sessions Cole - Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MissouriShawn O'Connor - Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MissouriGregory M Cooper - HudsonAlpha Institute for Biotechnology, Huntsville, AlabamaRudy Van Coster - Department of Pediatrics, Division of Pediatric Neurology and Metabolism, University Hospital Gent, Gent, BelgiumLaurie A Demmer - Clinical Genetics Program, Carolinas Health Care, Levine Childrens Hospital, Charlotte, North CarolinaLuisa Diogo - Centro de Desenvolvimento da Criança- Pediatric Hospital - CHUC, Coimbra, PortugalAlexander J Fay - Division of Pediatric Neurology, Washington University, St. Louis, MissouriCan Ficicioglu - Department of Pediatrics, Section of Metabolic Disease, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania Philadelphia, PennsylvaniaAgata Fiumara - Centre for Inherited Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Catania, Catania, ItalyWilliam A Gahl - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MarylandRebecca Ganetzky - Department of Pediatrics, Section of Metabolic Disease, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania Philadelphia, PennsylvaniaHimanshu Goel - Hunter Genetics, Waratah, New South Wales, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, AustraliaLyndsay A Harshman - Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, IowaMiao He - Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PennsylvaniaJaak Jaeken - Center for Metabolic Diseases, University Hospital of Leuven, Leuven, BelgiumPhilip M James - Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, ArizonaDaniel Katz - Pediatric Neurology, Stormont-Vail Health Care, Topeka, KansasLiesbeth Keldermans - Center for Human Genetics, University of Leuven, Leuven, BelgiumMaria Kibaek - Department of Pediatrics, Odense University Hospital, Odense, DenmarkAndrew J Kornberg - Department of Neurology, Royal Children's Hospital, Parkville, Victoria, AustraliaKatherine Lachlan - Human Genetics and Genomic Medicine, University of Southampton and Wessex Clinical Genetics Service, Southampton, United KingdomChristina Lam - National Human Genome Research Institute, NIH, Bethesda, MarylandJoy Yaplito-Lee - Department of Metabolic Medicine, Royal Children's Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, AustraliaDeborah A Nickerson - Department of Genome Sciences, University of Washington, Seattle, WashingtonHeidi L Peters - Department of Metabolic Medicine, Royal Children's Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, AustraliaValerie Race - Center for Human Genetics, University of Leuven, Leuven, BelgiumLuc Régal - Department of Pediatric Neurology and Metabolism, University Hospital of Brussels, Brussels, BelgiumJeffrey S Rush - Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KentuckyS Lane Rutledge - Department of Genetics, University of Alabama at Birmingham, Birmingham, AlabamaJay Shendure - Howard Hughes Medical Institute, University of Washington, Seattle, WashingtonErika Souche - Center for Human Genetics, University of Leuven, Leuven, BelgiumSusan E Sparks - Carolinas Healthcare System, Charlotte, North CarolinaPamela Trapane - Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, IowaAmarilis Sanchez-Valle - Division of Genetics and Metabolism, University of South Florida, Tampa, FloridaEric Vilain - Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CaliforniaArve Vøllo - Department of Pediatrics, Hospital of Ostfold N-1603 Fredrikstad, NorwayCharles J Waechter - Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KentuckyRaymond Y Wang - Department of Pediatrics, University of California-Irvine School of Medicine, Orange, CaliforniaLynne A Wolfe - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MarylandDerek A Wong - Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CaliforniaTim Wood - Greenwood Genetic Center, Greenwood, South CarolinaAmy C Yang - Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai, New York, New YorkGert Matthijs - Center for Human Genetics, University of Leuven, Leuven, BelgiumHudson H Freeze - Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
- Resource Type
- Journal article
- Publication Details
- Human mutation, Vol.37(7), pp.653-660
- Publisher
- United States
- DOI
- 10.1002/humu.22983
- PMID
- 26931382
- PMCID
- PMC4907823
- ISSN
- 1059-7794
- eISSN
- 1098-1004
- Grant note
- R01 DK055615 / NIDDK NIH HHS U54 HG006493 / NHGRI NIH HHS UM1 HG006493 / NHGRI NIH HHS R01 DK099551 / NIDDK NIH HHS R01 GM102129 / NIGMS NIH HHS T32 GM008638 / NIGMS NIH HHS U01 HG007301 / NHGRI NIH HHS
- Language
- English
- Date published
- 07/2016
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Surgery
- Record Identifier
- 9984065388802771
Metrics
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