Format

Send to

Choose Destination
Hum Mutat. 2019 Jul;40(7):908-925. doi: 10.1002/humu.23731. Epub 2019 Apr 24.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Author information

1
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
3
Texas Children's Hospital, Houston, Texas.
4
Department of Clinical and Experimental Medicine, Child Neurology and Psychiatry, University of Catania, Catania, Italy.
5
CNR, Institute for Polymers, Composites and Biomaterials, Catania, Italy.
6
Departments of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah.
7
Department of Pediatrics, University of Illinois College of Medicine, Peoria, Illinois.
8
Department of Pathology, University of Utah, Salt Lake City, Utah.
9
Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
10
Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland.
11
Department of Metabolic Medicine, Queensland Children's Hospital, Brisbane, Australia.
12
Schools of Medicine, University of Queensland Brisbane, Griffith University Gold Coast, Brisbane, Australia.
13
Department of Pediatrics, University of Washington, Seattle, Washington.
14
Seattle Children's Hospital, Seattle, Washington.
15
Department of Human Genetics, UCLA, Los Angeles, California.
16
Department of Pediatrics, UCLA, Los Angeles, California.
17
Departments of Pediatrics, University of Washington, Seattle, Washington.
18
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
19
Department of Medical Genetics, Shodair Children's Hospital, Helena, Montana.
20
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
21
Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
22
Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland.
23
Danish Epilepsy Center-Filadelfia, Dianalund, Denmark.
24
APHP,Genetics Department, GH Pity Salpetriere, CRMR Intellectual Disabilities of Rare Causes, Sorbonne University, Paris, France.
25
Ambry Genetics, Aliso Viejo, California.
26
GeneDx, Gaithersburg, Maryland.
27
Center for Neurogenetics Brain and Mind Research Institute Weill Cornell Medicine, New York, New York.
28
Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, California.
29
Department of Metabolic Medicine, The Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.
30
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
31
Clinical Genetics and Neurogenetics, Centro Universitario Estacio de Ribeirao Preto, Ribeirao Preto, Brazil.
32
Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, San Francisco, California.
33
Neurology Division Children's Hospital Los Angeles, Los Angeles, California.
34
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California.
35
Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel, Germany.
36
Department of Psychiatry & Biobehavioral Sciences, UCLA, Los Angeles, California.
37
Laboratory of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
38
Institute for Society and Genetics, UCLA, Los Angeles, California.
39
Departments of Pediatrics & Neurology, Keck School of Medicine of University of Southern California, Los Angeles, California.
40
Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota.
41
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California.
42
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California.
43
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California.
44
Division of Genetics, Department of Pediatrics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, Michigan.
45
The University of Melbourne, Austin Health, Melbourne, Australia.
46
Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, Hong Kong SAR.
47
The University of Melbourne, Royal Children's Hospital, Florey Institute and Murdoch Children's Research Institute, Melbourne, Australia.
48
Department of Pediatrics, Division of Child Neurology, Weill Cornell Medicine, New York, New York.
49
Neurology & Pediatrics, University of California, San Francisco, California.
50
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Pediatric Neurology and Muscular Diseases Unit, G. Gaslini Institute, University of Genoa, Genova, Italy.
51
Paediatric Neurosciences Research Group, Royal Hospital for Children, Queen Elizabeth University Hospitals, Glasgow, UK.
52
Center for Genetic Medicine Research, Children's National Medical Center, Columbia, Washington.
53
Department of Pediatrics, Naval Medical Center, San Diego, California.
54
Department of Pediatrics, Genetics Division, LAC+USC Medical Center, University of Southern California, Los Angeles, California.
55
Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
56
Metabolic Unit, Great Ormond Street Hospital NHS Trust, Institute for Child Health UCL, London, UK.

Abstract

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

KEYWORDS:

UDP-galactose; congenital disorders of glycosylation; glycoside; nucleotide sugar transporter

PMID:
30817854
PMCID:
PMC6661012
[Available on 2020-07-01]
DOI:
10.1002/humu.23731

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center