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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 908-925 |
| Number of pages | 18 |
| Journal | Human mutation |
| Volume | 40 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2019 |
Funding
National Institutes of Health (NIH), Grant/ Award Number: R01DK099551; The Rocket Fund; National Science Center, Grant/Award Number: 2016/21/B/NZ5/00144; NIH (NINDS), Grant/Award Numbers: 5R01NS050375, 1R01NS058721 The authors thank the families for their continued support. TMP was funded by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. The authors thank Jamie Smolin for her assistance. A complete list of the members of the Undiagnosed Diseases Network is provided in the Supporting Information data. This work is supported by The Rocket Fund, National Institutes of Health (NIH) grants R01DK099551 (to H.H.F) and personal contributions from Bill and Dinah Ruch and from Liberty Ross and Jimmy Iovine. National Science Center, 2016/21/B/NZ5/00144 (to M.O.). The National Institute of Neurological Disorders and Stroke (NINDS) award number K08NS092898 and Jordan's Guardian Angels (to G.M.). WBD supported by grants 5R01NS050375 and 1R01NS058721 from the NIH (NINDS). Partially funded by the National Human Genome Research Institute Intramural Program. Research reported in this manuscript was partially supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. UDN Award Numbers: clinical sites: U01HG007709 (Baylor College of Medicine), U01HG007672 (Duke University), U01HG007690 (Harvard Teaching Hospitals), U01HG007708 (Stanford Medicine), U01HG007703 (University of California Los Angeles), U01HG007674 (Vanderbilt University); coordinating center: U01HG007530 (Harvard Medical School); sequencing cores: U01HG007942 (Baylor College of Medicine), U01HG007943 (HudsonAlpha Institute for Biotechnology); metabolomics core: U01TR001395 (Battelle Pacific Northwest Laboratories); model organisms screening center: U54NS093793 (Baylor College of Medicine). 19Department of Medical Genetics, Shodair Children’s Hospital, Helena, Montana 20Northwestern University Feinberg School of Medicine, Chicago, Illinois 21Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 22Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland This work is supported by The Rocket Fund, National Institutes of Health (NIH) grants R01DK099551 (to H.H.F) and personal contributions from Bill and Dinah Ruch and from Liberty Ross and Jimmy Iovine. National Science Center, 2016/21/B/NZ5/00144 (to M.O.). The National Institute of Neurological Disorders and Stroke (NINDS) award number K08NS092898 and Jordan’s Guardian Angels (to G.M.). WBD supported by grants 5R01NS050375 and 1R01NS058721 from the NIH (NINDS). Partially funded by the National Human Genome Research Institute Intramural Program. Research reported in this manuscript was partially supported by the NIH Common Fund, through the Office of Strategic Coordination/ Office of the NIH Director. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. UDN Award Numbers: clinical sites: U01HG007709 (Baylor College of Medicine), U01HG007672 (Duke University), U01HG007690 (Harvard Teaching Hospitals), U01HG007708 (Stanford Medicine), U01HG007703 (University of California Los Angeles), U01HG007674 (Vanderbilt University); coordinating center: U01HG007530 (Harvard Medical School); sequencing cores: U01HG007942 (Baylor College of Medicine), U01HG007943 (HudsonAlpha Institute for Biotechnology); metabo-lomics core: U01TR001395 (Battelle Pacific Northwest
Keywords
- UDP-galactose
- congenital disorders of glycosylation
- glycoside
- nucleotide sugar transporter
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)