Format

Send to

Choose Destination
See comment in PubMed Commons below
Hum Mutat. 2016 Jul;37(7):653-60. doi: 10.1002/humu.22983. Epub 2016 Mar 21.

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

Author information

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

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

PMID:
26931382
PMCID:
PMC4907823
DOI:
10.1002/humu.22983
[PubMed - in process]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Support Center