2. Academic Validation
  3. ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients

ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients

  • Hum Mutat. 2016 Jul;37(7):653-60. doi: 10.1002/humu.22983.
Bobby G Ng 1,  Sergey A Shiryaev 1,  Daisy Rymen 2 3,  Erik A Eklund 4,  Kimiyo Raymond 5,  Martin Kircher 6,  Jose E Abdenur 7 8,  Fusun Alehan 9,  Alina T Midro 10,  Michael J Bamshad 6 11,  Rita Barone 12,  Gerard T Berry 13,  Jane E Brumbaugh 14,  Kati J Buckingham 11,  Katie Clarkson 15,  F Sessions Cole 16,  Shawn O'Connor 16,  Gregory M Cooper 17,  Rudy Van Coster 18,  Laurie A Demmer 19,  Luisa Diogo 20,  Alexander J Fay 21,  Can Ficicioglu 22,  Agata Fiumara 23,  William A Gahl 24,  Rebecca Ganetzky 22,  Himanshu Goel 25,  Lyndsay A Harshman 14,  Miao He 26,  Jaak Jaeken 3,  Philip M James 27,  Daniel Katz 28,  Liesbeth Keldermans 2,  Maria Kibaek 29,  Andrew J Kornberg 30,  Katherine Lachlan 31,  Christina Lam 32,  Joy Yaplito-Lee 33,  Deborah A Nickerson 6,  Heidi L Peters 33,  Valerie Race 2,  Luc Régal 34,  Jeffrey S Rush 35,  S Lane Rutledge 36,  Jay Shendure 6 37,  Erika Souche 2,  Susan E Sparks 38,  Pamela Trapane 14,  Amarilis Sanchez-Valle 39,  Eric Vilain 40 41,  Arve Vøllo 42,  Charles J Waechter 35,  Raymond Y Wang 7 8,  Lynne A Wolfe 24,  Derek A Wong 41,  Tim Wood 15,  Amy C Yang 43,  University of Washington Center for Mendelian Genomics,  Gert Matthijs 2,  Hudson H Freeze 1
Affiliations

Affiliations

  • 1 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
  • 2 Center for Human Genetics, University of Leuven, Leuven, Belgium.
  • 3 Center for Metabolic Diseases, University Hospital of Leuven, Leuven, Belgium.
  • 4 Section of Experimental Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 5 Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota.
  • 6 Department of Genome Sciences, University of Washington, Seattle, Washington.
  • 7 Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California.
  • 8 Department of Pediatrics, University of California-Irvine School of Medicine, Orange, California.
  • 9 Division of Pediatric Neurology, Baskent University School of Medicine, Ankara, Turkey.
  • 10 Department of Clinical Genetics, Medical University, Bialystok, Poland.
  • 11 Department of Pediatrics, University of Washington, Seattle, Washington.
  • 12 Pediatric Neurology Policlinico, University of Catania, Catania, Italy.
  • 13 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
  • 14 Stead Family Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, Iowa.
  • 15 Greenwood Genetic Center, Greenwood, South Carolina.
  • 16 Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
  • 17 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama.
  • 18 Department of Pediatrics, Division of Pediatric Neurology and Metabolism, University Hospital Gent, Gent, Belgium.
  • 19 Clinical Genetics Program, Carolinas Health Care, Levine Childrens Hospital, Charlotte, North Carolina.
  • 20 Centro de Desenvolvimento da Criança- Pediatric Hospital - CHUC, Coimbra, Portugal.
  • 21 Division of Pediatric Neurology, Washington University, St. Louis, Missouri.
  • 22 Department of Pediatrics, Section of Metabolic Disease, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania.
  • 23 Centre for Inherited Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
  • 24 NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, Maryland.
  • 25 Hunter Genetics, Waratah, New South Wales, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
  • 26 Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • 27 Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona.
  • 28 Pediatric Neurology, Stormont-Vail Health Care, Topeka, Kansas.
  • 29 Department of Pediatrics, Odense University Hospital, Odense, Denmark.
  • 30 Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
  • 31 Human Genetics and Genomic Medicine, University of Southampton and Wessex Clinical Genetics Service, Southampton, United Kingdom.
  • 32 National Human Genome Research Institute, NIH, Bethesda, Maryland.
  • 33 Department of Metabolic Medicine, Royal Children's Hospital, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
  • 34 Department of Pediatric Neurology and Metabolism, University Hospital of Brussels, Brussels, Belgium.
  • 35 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky.
  • 36 Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
  • 37 Howard Hughes Medical Institute, University of Washington, Seattle, Washington.
  • 38 Carolinas Healthcare System, Charlotte, North Carolina.
  • 39 Division of Genetics and Metabolism, University of South Florida, Tampa, Florida.
  • 40 Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
  • 41 Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
  • 42 Department of Pediatrics, Hospital of Ostfold N-1603 Fredrikstad, Norway.
  • 43 Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai, New York, New York.
PMID: 26931382 DOI: 10.1002/humu.22983
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.

Keywords

CDG; asparagine-linked glycosylation protein 1; carbohydrate-deficient transferrin; xeno-tetrasaccharide.

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