title: Mutations in STT3A and STT3B cause two congenital disorders of glycosylation.
abstract: We describe two unreported types of congenital disorders of glycosylation (CDG) which are caused by mutations in different isoforms of the catalytic subunit of the oligosaccharyltransferase (OST). Each isoform is encoded by a different gene (STT3A or STT3B), resides in a different OST complex and has distinct donor and acceptor substrate specificities with partially overlapping functions in N-glycosylation. The two cases from unrelated consanguineous families both show neurologic abnormalities, hypotonia, intellectual disability, failure to thrive and feeding problems. A homozygous mutation (c.1877T > C) in STT3A causes a p.Val626Ala change and a homozygous intronic mutation (c.1539 + 20G > T) in STT3B causes the other disorder. Both mutations impair glycosylation of a GFP biomarker and are rescued with the corresponding cDNA. Glycosylation of STT3A- and STT3B-specific acceptors is decreased in fibroblasts carrying the corresponding mutated gene and expression of the STT3A (p.Val626Ala) allele in STT3A-deficient HeLa cells does not rescue glycosylation. No additional cases were found in our collection or in reviewing various databases. The STT3A mutation significantly impairs glycosylation of the biomarker transferrin, but the STT3B mutation only slightly affects its glycosylation. Additional cases of STT3B-CDG may be missed by transferrin analysis and will require exome or genome sequencing.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Shiteshu
authors.initials: S
authors.lastname: Shrimal
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.forename: Marie-Estelle
authors.initials: ME
authors.lastname: Losfeld
authors.forename: Reid
authors.initials: R
authors.lastname: Gilmore
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002675:Child, Preschool; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D005260:Female; D006031:Glycosylation; D006367:HeLa Cells; D006602:Hexosyltransferases / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D013379:Substrate Specificity; D014168:Transferrin / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D014168:Transferrin; D006602:Hexosyltransferases; C099573:STT3A protein, human; C551978:STT3B protein, human