Molecular characteristics

Type of mutations
The only pathogenic variant reported so far in the CAMLG gene is an autosomal recessive variant affecting splicing (c.633+4A>G). This was shown by Wilson et al. (2022) to result in skipping of exon 2 of CAMLG and a lack of functional protein.

Genetic testing
If a CDG is suspected, isoelectric focusing of serum transferrin is recommended as a screening test. The individual with CAMLG-CDG described had a type 2 serum transferrin isoelectrofocusing pattern. Analysis of apoC-III glycoforms should also be performed to assess O-glycosylation and was also found abnormal in the only described patient. The next step is to perform CDG gene panel testing, or exome sequencing.

Suspected pathomechanism
The CAMLG gene encodes the CAML protein, a member of the transmembrane domain recognition complex (TRC) pathway. This pathway is required for the insertion of C-terminal tail-anchored (TA) proteins into the lipid bilayer of specific intracellular organelles such as the endoplasmic reticulum (ER) membrane. In order to facilitate correct insertion, the recognition complex (consisting of BAG6, GET4 and UBL4A) must first bind to TA proteins and then to GET3 (TRC40, ASNA1) which chaperones the protein to the ER membrane. Subsequently, GET1 (WRB) and CAML form a receptor which enables integration of the TA protein within the lipid bilayer.

It is currently thought that mutations in CAMLG lead to a combined trafficking and glycosylation disorder because certain TRC pathway substrates (such as the SNARE STX5) are incorrectly targeted. This leads to the gross phenotype observed in the affected individual reported.