The glycan-specific sulfotransferase (R77W)GalNAc-4-ST1 putatively responsible for peeling skin syndrome has normal properties consistent with a simple sequence polymorphisim

• Published in: Glycobiology (Oxford) 2017-05, Vol.27 (5), p.450-456
• Main Authors: Fiete, Dorothy, Mi, Yiling, Beranek, Mary, Baenziger, Nancy L, Baenziger, Jacques U
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dermatitis, Exfoliative - enzymology; Dermatitis, Exfoliative - genetics; Glycosaminoglycans - genetics; Glycosaminoglycans - metabolism; Humans; Microsatellite Repeats - genetics; Mutation, Missense; Oligosaccharides - genetics; Oligosaccharides - metabolism; Original articles; Polymorphism, Genetic; Polysaccharides - genetics; Polysaccharides - metabolism; Skin Diseases, Genetic - enzymology; Skin Diseases, Genetic - genetics; Sulfotransferases - genetics; Sulfotransferases - metabolism
• ISSN: 0959-6658; 1460-2423
• DOI: 10.1093/glycob/cwx018

Expanded access to DNA sequencing now fosters ready detection of site-specific human genome alterations whose actual significance requires in-depth functional study to rule in or out disease-causing mutations. This is a particular concern for genomic sequence differences in glycosyltransferases, whose implications are often difficult to assess. A recent whole-exome sequencing study identifies (c.229 C > T) in the GalNAc-4-ST1 glycosyltransferase (CHST8) as a disease-causing missense R77W mutation yielding the genodermatosis peeling skin syndrome (PSS) when homozygous. Cabral et al. (Genomics. 2012;99:202-208) cite this sequence change as reducing keratinocyte GalNAc-4-ST1 activity, thus decreasing glycosaminoglycan sulfation, as the mechanism for this blistering disorder. Such an identification could point toward potential clinical and/or prenatal diagnosis of a harmful medical condition. However, GalNAc-4-ST1 has minimal activity toward glycosaminoglycans, instead modifying terminal β1,4-linked GalNAc on N- and O-linked oligosaccharides on specific glycoproteins. We find expression, processing and catalytic activity of GalNAc-4-ST1 completely equivalent between wild type and (R77W) sulfotransferases. Moreover, keratinocytes have little or no GalNAc-4-ST1 mRNA, indicating that they do not express GalNAc-4-ST1. In addition, loss-of-function of GalNAc-4-ST1 primarily presents as reproductive system aberrations rather than skin effects. These findings, an allele frequency of 0.004357, and a 10-fold difference in prevalence of CHST8 (c.299 C > T, R77W) across different ethnic groups, suggest that this sequence represents a "passenger" distributed polymorphism, a simple sequence variant form of the enzyme having normal activity, rather than a "driver" disease-causing mutation that accounts for PSS. This study presents an example for guiding biomedical research initiatives, as well as medical and personal/family perspectives, regarding newly-identified genomic sequence differences.