Type of mutations
Both autosomal dominant and autosomal recessive forms of STT3A-CDG have been described and should be taken into account when considering a diagnosis.
List of mutations
Heterozygous (dominant STT3A-CDG)
Sixteen individuals from 9 families, with 7 different mutations have been reported. All of these mutations are missense variants, close to the catalytic site of the STT3A protein. Both inherited and de novo variants have been described.
c.137A>G; p.(His46Arg) – 1 individual, de novo
c.479G>A; p.(Arg160Gln) – 1 individual, de novo
c.985C>T; p.(Arg329Cys) – 2 individuals, 1 family, inherited
c.1213C>T; p.(Arg405Cys) – 3 individuals, 3 families, de novo
c.1214G>A; p.(Arg405His) – 4 individuals, 1 family, inherited
c.1589A>C; p.(Tyr530Ser) – 2 individuals, 1 family, inherited
c.1637C>T; p.(Thr546Ile) – 3 individuals, 1 family, inherited
Homozygous (autosomal recessive STT3A-CDG)
Eight individuals from 3 families, with 2 different mutations have been reported. Both missense variants are thought to result in reduced stability of the STT3A protein.
c.1877T > C; p.(Val626Ala) – 7 individuals, 2 families
c.1079A>C; p.(Tyr360Ser) – 1 individual
Genetic testing
If a CDG is suspected, isoelectric focusing of serum transferrin is recommended as a screening test. All individuals with STT3A-CDG described so far have had a type 1 serum transferrin isoelectrofocusing pattern. The next step is to perform a CDG gene panel, or exome sequencing. Variants of unknown significance in STT3A should be tested in vitro to confirm pathogenicity.
Suspected pathomechanism
STT3A encodes the catalytic subunit of the oligosaccharyltransferase (OST) complex. This means that deleterious mutations interfere with the transfer of the N-glycans from the lipid-linked oligosaccharide (LLO) onto recipient glycoproteins, resulting in a Congenital Disorder of Glycosylation.
In dominant STT3A-CDG, all mutations identified so far are close to the catalytic site. The mechanism here is thought to be a dominant-negative effect, where nascent glycoproteins pass through the OST but are left underglycosylated due to inefficient N-glycan transfer.
In autosomal recessive STT3A-CDG, the pathomechanism is thought to be instability of the STT3A protein, leading to reduced steady state levels of STT3A (and thus of the OST), causing insufficient oligosaccharyltransferase activity.
STT3A