TY - JOUR
T1 - Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency
AU - Van Scherpenzeel, Monique
AU - Timal, Sharita
AU - Rymen, Daisy
AU - Hoischen, Alexander
AU - Wuhrer, Manfred
AU - Hipgrave-Ederveen, Agnes
AU - Grunewald, Stephanie
AU - Peanne, Romain
AU - Saada, Ann
AU - Edvardson, Shimon
AU - Grønborg, Sabine
AU - Ruijter, George
AU - Kattentidt-Mouravieva, Anna
AU - Brum, Jaime Moritz
AU - Freckmann, Mary-Louise
AU - Tomkins, Susan
AU - Jalan, Anil
AU - Prochazkova, Dagmar
AU - Ondruskova, Nina
AU - Hansikova, Hana
AU - Willemsen, Michel A
AU - Hensbergen, Paul J
AU - Matthijs, Gert
AU - Wevers, Ron A
AU - Veltman, Joris A
AU - Morava, Eva
AU - Lefeber, Dirk J
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Child, Preschool
KW - DNA Mutational Analysis
KW - Female
KW - Glycosylation
KW - Humans
KW - Infant
KW - Intellectual Disability
KW - Male
KW - Membrane Proteins
KW - Mutation
KW - Nuclear Proteins
KW - Young Adult
U2 - 10.1093/brain/awu019
DO - 10.1093/brain/awu019
M3 - Journal article
C2 - 24566669
SN - 0006-8950
VL - 137
SP - 1030
EP - 1038
JO - Brain
JF - Brain
IS - Pt 4
ER -