title: Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome.
abstract: Adams-Oliver syndrome (AOS) is a rare, autosomal-dominant or -recessive disorder characterized primarily by aplasia cutis congenita and terminal transverse limb defects. Recently, we demonstrated that homozygous mutations in DOCK6 cause an autosomal-recessive form of AOS. In this study, we sought to determine the contribution of DOCK6 mutations to the etiology of AOS in several consanguineous families. In two of the five families studied, we identified two homozygous truncating mutations (a splice-site mutation and a frameshift duplication). DOCK6 sequencing revealed no mutation in the remaining three families, consistent with their autozygosity mapping and linkage-analysis results, which revealed a single candidate locus in 3p14.1 on three different haplotype backgrounds in the three families. Indeed, exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins. It has a documented role in epithelial-cell-matrix interactions in Drosophila, in which deficiency of its ortholog causes wing blistering. Our findings highlight a developmental role of O-GlcNAcylation in humans and expand the genetic heterogeneity of autosomal-recessive AOS.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.forename: Kim
authors.initials: K
authors.lastname: Keppler-Noreuil
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.forename: Shinu
authors.initials: S
authors.lastname: Ansari
authors.forename: Kim
authors.initials: K
authors.lastname: Horton
authors.forename: Adel
authors.initials: A
authors.lastname: Ashour
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Fatema
authors.initials: F
authors.lastname: Al-Zahrani
authors.forename: Anna M
authors.initials: AM
authors.lastname: Cueto-González
authors.forename: Ghada
authors.initials: G
authors.lastname: Abdel-Salam
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004476:Ectodermal Dysplasia / Q000209:etiology*; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D017880:Limb Deformities, Congenital / Q000209:etiology*; D008297:Male; D009154:Mutation / Q000235:genetics*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D012536:Scalp Dermatoses / Q000151:congenital* / Q000209:etiology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C000617979:EOGT protein, human; D017351:N-Acetylglucosaminyltransferases