Understanding human glycosylation disorders: biochemistry leads the charge

Abstract

Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration.

FIGURE 1.

Schematic of the N-glycosylation pathway. The upper oval represents the ER. The early steps involve GlcNAc (blue squares), Glc (blue circles), and Man (green circles) addition to an LLO assembly on Dol-P (red circles with wavy green lines) using UDP-GlcNAc (orange star with blue square) and GDP-Man (orange star with green circle) donors on the cytoplasmic face. The partially completed glycan flips to the luminal side, where it is completed using the donors Dol-P-Man (large green circle with small red circle and wavy green line) and Dol-P-Glc (large blue circle with small red circle and wavy green line) to form Glc₃Man₉GlcNAc₂-P-P-Dol, which is then transferred to proteins in the ER. The lower oval denotes processing of the N-glycans using a series of glycosidases and glycosyltransferases that require UDP-GlcNAc (orange star with blue square), UDP-Gal (orange star with yellow circle), and CMP-Sia (orange star with purple diamond) transported into the Golgi. Purple diamonds, sialic acid; yellow circles, galactose.

FIGURE 2.

GPI anchor synthesis. This schematic shows the stepwise pathway for GPI anchor assembly, including the reaction and the names of the enzymes and genes involved. Known glycosylation disorders are highlighted in red. White and blue squares, glucosamine; EtNP (N connected to P with bent lines), ethanolamine phosphate; GlcNAc-PI, N-acetylglucosaminylphosphatidylinositol. This figure was adapted from Ref. .

FIGURE 3.

Monosaccharide metabolism in mammals and human glycosylation disorders. The gray oval indicates the ER, and all other reactions are thought to occur in the cytoplasm. The purple asterisks indicate known points of metabolic regulations. This figure was adapted from Ref. .