title: Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency.
abstract: Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of intellectual disability, caused by deficient glycosylation of proteins and lipids. The molecular basis of the majority of the congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with intellectual disability, whole-exome sequencing revealed MAN1B1 as congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-glycans, in agreement with deficient mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-glycans were also observed in the glycoprofiles of total serum proteins, of enriched immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal obesity and macrocephaly in ∼65% of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved congenital disorder of glycosylation type II. Our method for analysis of intact transferrin provides a rapid test to detect MAN1B1-deficient patients within congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with intellectual disability.
authors.affiliation: 1 Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Van Scherpenzeel
authors.forename: Sharita
authors.initials: S
authors.lastname: Timal
authors.forename: Daisy
authors.initials: D
authors.lastname: Rymen
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
authors.forename: Agnes
authors.initials: A
authors.lastname: Hipgrave-Ederveen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grunewald
authors.forename: Romain
authors.initials: R
authors.lastname: Peanne
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Shimon
authors.initials: S
authors.lastname: Edvardson
authors.forename: Sabine
authors.initials: S
authors.lastname: Grønborg
authors.forename: George
authors.initials: G
authors.lastname: Ruijter
authors.forename: Anna
authors.initials: A
authors.lastname: Kattentidt-Mouravieva
authors.forename: Jaime Moritz
authors.initials: JM
authors.lastname: Brum
authors.forename: Mary-Louise
authors.initials: ML
authors.lastname: Freckmann
authors.forename: Susan
authors.initials: S
authors.lastname: Tomkins
authors.forename: Anil
authors.initials: A
authors.lastname: Jalan
authors.forename: Dagmar
authors.initials: D
authors.lastname: Prochazkova
authors.forename: Nina
authors.initials: N
authors.lastname: Ondruskova
authors.forename: Hana
authors.initials: H
authors.lastname: Hansikova
authors.forename: Michel A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hensbergen
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
mesh_terms: D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins; D005260:Female; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C405329:LEMD3 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins
keywords: MAN1B1 (EC 3.2.1.113); biomarker; congenital disorders of glycosylation; glycomics; intellectual disability