A glycogene mutation map for discovery of diseases of glycosylation

Abstract

Glycosylation of proteins and lipids involves over 200 known glycosyltransferases (GTs), and deleterious defects in many of the genes encoding these enzymes cause disorders collectively classified as congenital disorders of glycosylation (CDGs). Most known CDGs are caused by defects in glycogenes that affect glycosylation globally. Many GTs are members of homologous isoenzyme families and deficiencies in individual isoenzymes may not affect glycosylation globally. In line with this, there appears to be an underrepresentation of disease-causing glycogenes among these larger isoenzyme homologous families. However, genome-wide association studies have identified such isoenzyme genes as candidates for different diseases, but validation is not straightforward without biomarkers. Large-scale whole-exome sequencing (WES) provides access to mutations in, for example, GT genes in populations, which can be used to predict and/or analyze functional deleterious mutations. Here, we constructed a draft of a functional mutational map of glycogenes, GlyMAP, from WES of a rather homogenous population of 2000 Danes. We cataloged all missense mutations and used prediction algorithms, manual inspection and in case of carbohydrate-active enzymes family GT27 experimental analysis of mutations to map deleterious mutations. GlyMAP (http://glymap.glycomics.ku.dk) provides a first global view of the genetic stability of the glycogenome and should serve as a tool for discovery of novel CDGs.

Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

“…Genetic deficiency in GALNT11 has not been identified so far in man and it is predicted to be extremely rare if occurring (34), but GALNT11 has been identified as a GWAS candidate gene for chronic kidney decline (46). The GWAS signal for chronic kidney decline resides in intron one of the GALNT11 gene, suggesting that the genetic predisposition is a result of altered gene regulation, similar to what has been established for the role of GALNT2 in dyslipidemia (19,47).…”

Precise integration of inducible transcriptional elements (PrIITE) enables absolute control of gene expression

“…Of notice, the only glycogenes (49) otherwise affected by CDX2 were FUT3 and GALNT1 which in the latter case responded inversely to CDX2 changes (Figure 5B). …”

Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents

“…This report suggested that this variant modestly reduces catalytic activity of GalNAc-T2 as measured by an in vitro enzymatic assay. However, a subsequent identification of this variant in a cohort of 2,000 Danes and functional testing showed the variant to confer normal enzymatic activity (Hansen et al, 2015). Because the 2011 report identified the variant in 2 high HDL-C probands and an additional 6 heterozygotes with normal HDL-C levels, we wondered if identification of additional carriers of this variant and potentially homozygotes would help us better determine the relationship of this variant to HDL-C levels and any allele-dosage effect of the variant on this trait.…”