By: Richard D. Cummings
Among the 900-1,400 genes on the human X chromosome (1, 2)[1], there are many genes important in the metabolism of glycomolecules, including glycosyltransferases, glycohydrolases, transporters, and chaperones. Mutations in several of these X-linked genes, either heritable or acquired (de novo), are associated with Congenital Disorders of Glycosylation (CDG) (3) and Lysosomal Storage Disorders (LSDs) (4). A list of all known diseases associated with defects on the X chromosome may be found at https://www.ncbi.nlm.nih.gov/gdv/browser/genome/?id=GCF_000001405.40&chr=X.
A list of the glyco-related genes is provided below. This list is not comprehensive but provides an overview of many glycosylation-related disorders arising from mutations in genes on the X-chromosome.
Transferases –
- UDP-GlcNAc: polypeptide O-β-N-acetylglucosaminyltransferase (OGT) (Xq13.1) generates O-GlcNAc modifications on intracellular glycoproteins (5, 6). Heritable mutations in OGT are associated with OGT-CDG (7-11) and patients with this often present with intellectual disability (ID) syndrome termed OGT congenital disorder of glycosylation (OGT-CDG) (12, 13). Consequences of mutation in OGT can be multiple and severe, as O-GlcNAcylation affects many pathways of cell signaling and differentiation.
- Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) (Xp22.2) initiates GPI-anchor biosynthesis by addition of GlcNAc to phosphatidylinositol (14). Heritable X-linked mutations in PIGA result in PIGA-CDG (15, 16). This defect is also termed multiple congenital anomalies-hypotonia seizures syndrome 2. However, mutations in PIGA can be acquired (de novo), whereby mutations in hematopoietic stems cells create cell lineages in a mosaic presentation, and patients present with Paroxysmal Nocturnal Hemoglobinuria (PNH) disease (17-19).
- UDP-N-acetylglucosaminyltransferase subunit (ALG13) transfers GlcNAc from UDP-GlcNAc to Dol-P-P-GlcNAc to synthesize Dol-P-P-GlcNAc2 (Xq23) (20, 21). Heritable mutations in this gene are associated with ALG13-CDG (22).
- Heparin sulfate 6-O-sulfotransferase 2 (HS6ST2) (Xq26.2) adds sulfate to glucuronate residues at the 6-O position in heparan sulfate (23). Heritable mutations in this gene are associated with HS6ST2-CDG (24).
- Carbohydrate sulfotransferase 7 (CHST7) (Xp11.3) catalyzes the sulfation of 6-hydroxyl group of GalNAc in chondroitin (25).
- Glycogenin 2 (GYG2) (Xp22.33) self-initiates glycogen production by glucosylation of internal tyrosine residues via UDP-Glc (26). Hemizygous mutations in GYG2 have been associated with Leigh syndrome (27), but individuals with a deletion (114-kb deletion) of a portion of the X-chromosome in which this gene is located have also been identified (28).
Glycosidase –
- α-Galactosidase 1 (GLA) (Xq22.1) hydrolyses the α-linked galactose on glycolipids (29). Heritable mutations in this gene are associated with Fabry disease (30), an LSD associated with the accumulation of globotriaosylceramide in lysosomes.
Transporters –
- UDP-galactose transporter known as solute carrier family 35 member A2 (SLC35A2) (Xp11.23) transports UDP-Gal into the Golgi apparatus (31). Heritable mutations in this gene are associated with SLC35A2-CDG (32).
- ATPase H+ transporting accessory protein 1 (ATP6AP1) (Xp28) is important in the folding and assembly of V-ATPase, that helps to maintain Golgi pH homeostasis (33, 34). Hemizygous missense mutations in ATP6AP1 are associated with hepatopathy, cognitive impairment and abnormal protein glycosylation (34, 35).
- The SLC9A7 gene (Xp11.3) encodes a sodium/potassium/proton antiporter 7 (NHE7), and mutations in this gene are associated with altered pH of the Golgi and altered glycosylation (36). It is one of the X-linked genes implicated in Alzheimer’s disease (37).
Chaperone –
- Cosmc (C1GALT1C1 or COSMC) (Xq24) is the chaperone for the T-synthase and is required for formation of the active enzyme (C1GALT1) (38). Heritable mutations in this gene are associated with COSMC-CDG (39). Acquired (de novo) mutations in COSMC also occur in patients who are genetically mosaic as a consequence (40). Mutation of COSMC in hematopoietic stem cells creates blood cell lineages in a mosaic presentation whereby patients present with Tn Syndrome (41).
Others –
- Signal sequence receptor protein 4 (SSR4) (Xq28) is a subunit (TRAP δ) of the heterotetrameric translocon-associated protein (TRAP) complex (42). SSR4 is needed for the translocation of proteins across the membrane of the endoplasmic reticulum, which enhances the efficiency of their N-linked glycosylation (43). Heritable mutations in this gene are associated with SSR4-CDG (44-46).
- Xg glycoprotein (Xg blood group) (XG) (Xp22.33) encodes the Xg(a+) and Xg(a−) blood group; this is a glycoprotein expressing from either the a+ or a- allele, and is the only human blood system where the antigen-encoding genes are located on the X chromosome (47, 48).
- Glucose-6-phosphate dehydrogenase (G6PD) (Xq28) converts Glc-6-P to 6-phosphogluconate (6PG), the first committed step in the Pentose Phosphate Pathway (PPP). This drives the production of NADPH in the presence of NADP. G6PD is the most common human enzyme defect known, affecting upward of 400 million people worldwide (49). To date, there are 186 known human G6PD mutations, and most are point mutations affecting a single nucleotide. This is the only pathway in red blood cells to produce NADPH (50). [Interestingly, G6PD is modified by O-GlcNAc (OGT) in response to hypoxia, which generates metabolites important as anti-oxidants (51).]
- Collagen type IV alpha 5 chain (COL4A5) (Xq22.3) encodes the alpha 5 chain in basement membrane type IV collagen; mutations in this gene are associated with X-linked Alport syndrome (52).
- Collagen type IV alpha 6 chain (COL4A6) (Xq22.3) encodes the alpha 6 chain in basement membrane type IV collagen. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene COL4A5 (53).
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