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Publication : Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome.

First Author  Shaheen R Year  2013
Journal  Am J Hum Genet Volume  92
Issue  4 Pages  598-604
PubMed ID  23522784 Mgi Jnum  J:203640
Mgi Id  MGI:5528419 Doi  10.1016/j.ajhg.2013.02.012
Citation  Shaheen R, et al. (2013) Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome. Am J Hum Genet 92(4):598-604
abstractText  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.
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