N-glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency.
Adolescent
Basal Ganglia
/ physiopathology
Cation Transport Proteins
/ deficiency
Child
Child, Preschool
Chromatography, High Pressure Liquid
Congenital Disorders of Glycosylation
/ genetics
Female
Glycosylation
Humans
Infant
Magnetic Resonance Imaging
Male
Manganese
/ metabolism
Mass Spectrometry
Phenotype
Transferrin
/ analysis
Exome Sequencing
Young Adult
MALDI-TOF MS
SLC39A8
congenital disorders of glycosylation
glycosylation
manganese
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
24
06
2020
revised:
07
08
2020
accepted:
26
08
2020
pubmed:
28
8
2020
medline:
8
10
2021
entrez:
28
8
2020
Statut:
ppublish
Résumé
Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8-CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of N-glycosylation is the analysis of serum transferrin. Exome and Sanger sequencing were performed in two patients with severe neurodevelopmental phenotypes suggestive of CDG. Transferrin glycosylation was analyzed by high-performance liquid chromatography (HPLC) and isoelectric focusing in addition to comprehensive N-glycome analysis using matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS). Atomic absorption spectroscopy was used to quantify whole blood manganese levels. Both patients presented with a severe, multisystem disorder, and a complex neurological phenotype. Magnetic resonance imaging (MRI) revealed a Leigh-like syndrome with bilateral T2 hyperintensities of the basal ganglia. In patient 1, exome sequencing identified the previously undescribed homozygous variant c.608T>C [p.F203S] in SLC39A8. Patient 2 was found to be homozygous for c.112G>C [p.G38R]. Both individuals showed a reduction of whole blood manganese, though transferrin glycosylation was normal. N-glycome using MALDI-TOF MS identified an increase of the asialo-agalactosylated precursor N-glycan A2G1S1 and a decrease in bisected structures. In addition, analysis of heterozygous CDG-allele carriers identified similar but less severe glycosylation changes. Despite its reliance as a clinical gold standard, analysis of transferrin glycosylation cannot be categorically used to rule out SLC39A8-CDG. These results emphasize that SLC39A8-CDG presents as a spectrum of dysregulated glycosylation, and MS is an important tool for identifying deficiencies not detected by conventional methods.
Identifiants
pubmed: 32852845
doi: 10.1002/jimd.12306
pmc: PMC8086894
mid: NIHMS1692330
doi:
Substances chimiques
Cation Transport Proteins
0
SLC39A8 protein, human
0
Transferrin
0
Manganese
42Z2K6ZL8P
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1370-1381Subventions
Organisme : NIMH NIH HHS
ID : T32 MH112485
Pays : United States
Informations de copyright
© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
Références
Nat Commun. 2018 Oct 9;9(1):4171
pubmed: 30301978
Cell Mol Life Sci. 2002 Jul;59(7):1081-95
pubmed: 12222957
Int J Mol Sci. 2020 Jan 09;21(2):
pubmed: 31936666
Hum Genomics. 2019 Sep 14;13(Suppl 1):51
pubmed: 31521203
Sci Rep. 2020 Aug 4;10(1):13162
pubmed: 32753748
Neurotoxicology. 1999 Apr-Jun;20(2-3):213-23
pubmed: 10385885
N Engl J Med. 2014 Feb 6;370(6):533-42
pubmed: 24499211
Mol Psychiatry. 2020 Dec;25(12):3129-3139
pubmed: 32377000
Ann Transl Med. 2019 Sep;7(Suppl 6):S225
pubmed: 31656804
Clin Biochem. 2015 Jan;48(1-2):11-3
pubmed: 25305627
Blood. 1999 Dec 15;94(12):3976-85
pubmed: 10590041
Circulation. 2019 Jul 23;140(4):280-292
pubmed: 31117816
Orphanet J Rare Dis. 2019 Oct 22;14(1):231
pubmed: 31640729
Am J Hum Genet. 2015 Dec 3;97(6):894-903
pubmed: 26637979
Acta Paediatr. 1998 Aug;87(8):884-8
pubmed: 9736238
J Inherit Metab Dis. 2018 May;41(3):499-513
pubmed: 29497882
J Inherit Metab Dis. 2017 Mar;40(2):261-269
pubmed: 27995398
PLoS One. 2015 Jun 01;10(6):e0128045
pubmed: 26029922
Eur J Biochem. 1991 Jan 1;195(1):243-50
pubmed: 1899383
Gastroenterology. 2016 Oct;151(4):724-32
pubmed: 27492617
Genet Med. 2020 Jun;22(6):1102-1107
pubmed: 32103184
Genet Med. 2018 Feb;20(2):259-268
pubmed: 28749473
Nat Genet. 2004 Jan;36(1):40-5
pubmed: 14702039
Am J Hum Genet. 2015 Dec 3;97(6):886-93
pubmed: 26637978
Glycoconj J. 2016 Jun;33(3):297-307
pubmed: 26873821
Biochem Biophys Res Commun. 1992 Dec 15;189(2):832-6
pubmed: 1472054
Biol Pharm Bull. 2019;42(7):1076-1082
pubmed: 31257283
Glycoconj J. 2016 Jun;33(3):309-43
pubmed: 26555091
Hum Mol Genet. 2015 Aug 15;24(16):4739-45
pubmed: 26025379
Glycobiology. 2006 Feb;16(2):29R-37R
pubmed: 16037492
Free Radic Biol Med. 2013 Sep;62:4-12
pubmed: 23727323
Biol Trace Elem Res. 1986 Dec;11(1):201-12
pubmed: 24254514
Transl Psychiatry. 2019 Jan 29;9(1):45
pubmed: 30696806
Curr Top Cell Regul. 1984;24:153-69
pubmed: 6149889
J Clin Invest. 1998 Apr 1;101(7):1414-20
pubmed: 9525984