Title: Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency
Authors: Van Scherpenzeel, Monique ×
Timal, Sharita
Rymen, Daisy
Hoischen, Alexander
Wuhrer, Manfred
Hipgrave-Ederveen, Agnes
Grunewald, Stephanie
Peanne, Romain
Saada, Ann
Edvardson, Shimon
Grønborg, Sabine
Ruijter, George
Kattentidt-Mouravieva, Anna
Brum, Jaime Moritz
Freckmann, Mary-Louise
Tomkins, Susan
Jalan, Anil
Prochazkova, Dagmar
Ondruskova, Nina
Hansikova, Hana
Willemsen, Michel A
Hensbergen, Paul J
Matthijs, Gert
Wevers, Ron A
Veltman, Joris A
Morava, Eva
Lefeber, Dirk J #
Issue Date: Apr-2014
Publisher: Macmillan
Series Title: Brain vol:137 issue:Pt 4 pages:1030-1038
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.
ISSN: 0006-8950
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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