Autosomal recessive Adams–Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase

Abstract

Autosomal recessive Adams-Oliver syndrome was diagnosed in three remotely related Bedouin consanguineous families. Genome-wide linkage analysis ruled out association with known Adams-Oliver syndrome genes, identifying a singlehomozygosity B1.8-Mb novel locus common to affected individuals (LOD score 3.37). Whole-exome sequencing followed by Sanger sequencing identified only a single mutation within this locus, shared by all affected individuals and found in patients from five additional apparently unrelated Bedouin families: a 1-bp deletion mutation in a predicted alternative splice variant of EOGT, leading to a putative truncated protein. RT-PCR demonstrated that the EOGT-predicted alternative splice variant is ubiquitously expressed. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine transferase, responsible for extracellular O-GlcNAcylation of epidermal growth factor-like domain-containing proteins, and is essential for epithelial cell-matrix interactions. F-actin staining in diseased fibroblasts showed apparently intact cell cytoskeleton and morphology, suggesting the EOGT mutation acts not through perturbation of cytoskeleton but through other mechanisms yet to be elucidated.

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

“…However, additional experiments have uncovered a dosage-sensitive genetic interaction between several components of the Notch signaling pathway and Eogt knockdown adult flies (54). Moreover, mutations in human EOGT have been reported in an autosomal recessive form of a human disease called AdamsOliver syndrome (55,56). Notably, mutations in several Notch pathway components cause an autosomal dominant form of the same disease (39,40,(57)(58)(59).…”

N-acetylglucosamine modification in the lumen of the endoplasmic reticulum

“…The basic pathophysiologic mechanism in AOS remains unknown, but these defects are assumed to be due to a vasculopathy, because cardiovascular defects are occasionally observed in AOS patients. Indeed, cutis marmorata telangiectatica congenita (CMTC), atrial septal defect (ASD), and ventricular septal defect (VSD), caused by EOGT mutations, have been reported in some AOS patients [29,51].…”

“…Although the biological roles of extracellular O-GlcNAc in mammals have not been clarified, EOGT mutations have been reported in patients with Adams-Oliver syndrome (AOS) [29,51]. AOS is a rare congenital disorder characterized by aplasia cutis congenita (ACC) of the scalp vertex and terminal transverse limb defects (TTLDs) (Fig.…”

Impaired O-Linked N-Acetylglucosaminylation in the Endoplasmic Reticulum by Mutated Epidermal Growth Factor (EGF) Domain-specific O-Linked N-Acetylglucosamine Transferase Found in Adams-Oliver Syndrome

“…Impaired O-GlcNAcylation in EOGT Mutants Associated with AOS-Recently, the homozygous mutations in EOGT were identified in some patients with AOS (16,17). To date, three homozygous mutations for EOGT have been reported (Fig.…”

“…In contrast to the pivotal roles of extracellular O-GlcNAc in Drosophila development, much less is known regarding the biological requirement of EOGT in mammals (15). The first implication came from a recent report of an EOGT mutation in a rare human congenital disorder, AdamsOliver syndrome (AOS), which is characterized by aplasia cutis congenital and terminal transverse limb defects (16,17). The aim of this study was to biochemically analyze EOGT mutations linked to AOS and demonstrate that a defect in O-GlcNAcylation in the endoplasmic reticulum (ER) caused by EOGT mutations constitutes the molecular basis for AOS.…”