title: The glycan-specific sulfotransferase (R77W)GalNAc-4-ST1 putatively responsible for peeling skin syndrome has normal properties consistent with a simple sequence polymorphisim.
abstract: 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.
authors.affiliation: Departments of Biochemistry and Molecular Biophysics, and Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fiete
authors.affiliation: Departments of Biochemistry and Molecular Biophysics, and Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Departments of Biochemistry and Molecular Biophysics, and Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Beranek
authors.affiliation: Departments of Biochemistry and Molecular Biophysics, and Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Baenziger
authors.affiliation: Departments of Biochemistry and Molecular Biophysics, and Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Jacques U
authors.initials: JU
authors.lastname: Baenziger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D003873:Dermatitis, Exfoliative / Q000201:enzymology / Q000235:genetics*; D006025:Glycosaminoglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D020125:Mutation, Missense; D009844:Oligosaccharides / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011134:Polysaccharides / Q000235:genetics* / Q000378:metabolism; D012873:Skin Diseases, Genetic / Q000201:enzymology / Q000235:genetics*; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; D009844:Oligosaccharides; D011134:Polysaccharides; C092527:N-acetylgalactosamine-4-sulfotransferase; D015238:Sulfotransferases
keywords: CHST8; GalNAc-4-ST1; generalized peeling skin syndrome; glycans; mutation; sulfotransferase