Inheritance
The mode of inheritance is X-linked recessive. A Heterozygous female is unaffected and has a 50 % risk of having affected male offspring.
Mutation types
Mutation types include missense variants and a recurrent frameshift variant in the last exon of the gene escaping non-sense mediated decay. Loss-of-function variants have not been described to date in male patients and are considered not viable. The frameshift mutation generally causes a more severe phenotype. Variants so far reported are located in distinct regions of the protein and do not cluster in a specific protein domain.
Genetic testing
All reported pathogenic variants in the EIF2S3 gene are detectable by Sanger or short-read NGS sequencing analysis.
Possible molecular diagnostic approaches to confirm the diagnosis in a proband include:
• performing EIF2S3 Sanger sequencing (single-gene testing), if the clinical suspicion of EIF2S3-related syndrome is high;
• performing a multi-gene panel, which includes EIF2S3, or
• performing exome sequencing, if multiple differential diagnoses exist.
Suspected pathophysiologic mechanism
The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the integrated stress response.
During translation initiation, eIF2 binds GTP and the initiator methionyl-tRNA via eIF2γ, to form a ternary complex that scans mRNA for the AUG start codon and thereby initiates protein synthesis. The eIF2 factor also functions as central hub for regulation of integrated stress response – its function is downregulated by phosphorylation of the eIF2α subunit by PERK (unfolded-protein response), GCN2, PKR and HRI kinases in response to specific cellular stresses. Upon eIF2α phoshorylation, global translation is attenuated, but this leads also to increased translation of transcription factor ATF4 increasing expression of chaperons, components of ER-associated degradation system and, eventually, pro-apoptotic transcription factor CHOP.
Impairment of eIF2γ function causes decreased fidelity of start codon selection (enables ribosomes to initiate at non-AUG codons) and leads to a general insufficiency of protein synthesis that most significantly impacts processes requiring high rates of protein synthesis and increases sensitivity in states of elevated metabolic requirements.
EIF2S3