title: Transferrin mutations at the glycosylation site complicate diagnosis of congenital disorders of glycosylation type I.
abstract: Congenital disorders of glycosylation (CDG) form a group of metabolic disorders caused by deficient glycosylation of proteins and/or lipids. Isoelectric focusing (IEF) of serum transferrin is the most common screening method to detect abnormalities of protein N-glycosylation. On the basis of the IEF profile, patients can be grouped into CDG type I or CDG type II. Several protein variants of transferrin are known that result in a shift in isoelectric point (pI). In some cases, these protein variants co-migrate with transferrin glycoforms, which complicates interpretation. In two patients with abnormal serum transferrin IEF profiles, neuraminidase digestion and subsequent IEF showed profiles suggestive of the diagnosis of CDG type I. Mass spectrometry of tryptic peptides of immunopurified transferrin, however, revealed a novel mutation at the N-glycan attachment site. In case 1, a peptide with mutation p.Asn630Thr in the 2nd glycosylation site was identified, resulting in an additional band at disialotransferrin position on IEF. After neuraminidase digestion, a single band was found at the asialotransferrin position, indistinguishable from CDG type I patients. In case 2, a peptide with mutation p.Asn432His was found. These results show the use of mass spectrometry of transferrin peptides in the diagnostic track of CDG type I.
authors: Institute for Genetic and Metabolic Disease, Department of Laboratory Medicine / Department of Neurolog, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6525, GA, Nijmegen, The Netherlands.
authors: Mailys
authors: M
authors: Guillard
authors: Yoshinao
authors: Y
authors: Wada
authors: Hana
authors: H
authors: Hansikova
authors: Isao
authors: I
authors: Yuasa
authors: Katerina
authors: K
authors: Vesela
authors: Nina
authors: N
authors: Ondruskova
authors: Machiko
authors: M
authors: Kadoya
authors: Alice
authors: A
authors: Janssen
authors: Lambertus P W J
authors: LP
authors: Van den Heuvel
authors: Eva
authors: E
authors: Morava
authors: Jiri
authors: J
authors: Zeman
authors: Ron A
authors: RA
authors: Wevers
authors: Dirk J
authors: DJ
authors: Lefeber
mesh_terms: D020134:Catalytic Domain / Q000235:genetics; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007525:Isoelectric Focusing; D008297:Male; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014168:Transferrin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014168:Transferrin