Defining a new immune deficiency syndrome: MAN2B2-CDG

Abstract

We describe the first case of MAN2B2 deficiency in a patient with immune dysregulation, developmental delay, and stroke. Altered mannosylation profile was restored in patient cells upon transduction of wild-type MAN2B2.

Figure 1.. Abundance of Man2GlcNac2 and Man2Glcnac1 in patient fibroblasts is reversed upon lentivirus-mediated transfer of wild-type MAN2B2

A: Schematic representation of the lysosomal N-glycan degradation and monosaccharide salvage pathway. Released monosaccharides are reused as source for glycosylation in ER and Golgi. Figure adapted from . B: Sorting and recycling pathways of N-linked and GPI-anchored glycoproteins, and subsequent salvage pathway feeding into glycan biosynthesis. C: MALDI TOF spectra of permethylated N-glycans from patient fibroblasts, showing abundant glycans. D: Quantification of relative abundance of glycans in patient and control fibroblasts. Values are presented from MALDI TOF permethylated N-glycan profiles for patient fibroblasts and ten controls. Glycan identity is indicated for Man2GlcNac2. Blue square: N-acetylglucosamine (GlcNAc); green circle: mannose. E: MALDI TOF free glycan profiling shows increased abundance of Man2GlcNAc1 in patient fibroblasts. FOS: free oligosaccharide. F: Enzymatic 1,6 mannosidase digestion shows trimming of Man2GlcNAc1 to Man1GlcNac1, indicating that the pool of Man2GlcNac1 accumulated in patient fibroblasts carries core 1,6 mannose residues. G: N-linked glycan profiling in patient fibroblasts transduced with wild-type MAN2B2 lentiviral vector shows reduction of Man2GlcNac2 and Man3GlcNac2. H: Free glycan profiles in patient fibroblasts transduced with wild-type MAN2B lentiviral vector show reduction in relative abundance of Man2GlcNac1.