Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency
Abstrakt
Congenital disorders of glycosylation are associated with intellectual disability. Using a novel glycoprofiling method, Van Scherpenzeel et al. screened 100 patients with deficient glycosylation, and identified 12 patients with identical glycan abnormalities and mutations in MAN1B1.
The results provide functional confirmation of MAN1B1 variants in intellectual disability.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...