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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

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.

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
[Indexed for MEDLINE]
Free PMC Article

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