Molecular characteristics
EOGT is located at 3p14.1 and encodes an EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-linked N-acetylglucosamine to serine and threonine residues) of a category of extracellular EGF-domain-containing proteins. This posttranslational modification influences the stability of various proteins and regulates their role in various cellular mechanisms. It was demonstrated that the EOGT enzyme (ER resident O-GlcNac transferase) O-GlcNAcylates two membrane proteins essential for cell-extracellular matrix interactions, Dumpy and Notch, in Drosophila. Loss of Eogt (EOGT Dorsophilia ortholog) causes wing blistering, phenotypical of cell-cell adhesion and cell-matrix interaction dysregulation. Eogt has been found to be expressed in presomaitic mesoderm, the heart, lung, liver, spleen, and skeletal muscles. It was also found to be expressed in the apical ectodermal ridge of the limbs.
Mutations and pathophysiology
Shamseldin et al. (2013) identified homozygosity for a missense mutation in one individual from a consanguineous family: c.620G>C [p.Trp207Ser]; RefSeq NM_173654.1 and a missense mutation in three individuals from a different consanguineous family: c.1130G>A [p.Arg377Gln]. The study also identified a 1bp homozygous deletion creating a frameshift and premature stop codon (c.1074delA [p.Gly359Aspfs*28]) in one individual from a different consanguineous family.
A recent large European cohort study (Meester et al. 2018) identified five EOGT mutations: a homozygous splice site mutation, c.311+1G>T [p.?], two homozygous missense mutations, c.404G>A [p.Cys135Tyr] and c.1130G>A [p.Arg377Gln], the latter of which was also reported by Shamseldin et al. (2013), a compound heterozygous frameshift mutation, c.78_81delTCAC [p.His27Alafs*46], and a compound heterozygous splice site mutation, c.1335-1G>A [p.?].
It is suggested that EOGT mutations in humans cause AOS by causing dysregulation of cell-cell or cell-matrix interactions. The clinical features of this disorder are listed in the Clinical Characteristics section.