Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review

Abstract

Rare pathogenic EIF2S3 missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novel EIF2S3 pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of the EIF2S3 encoded eIF2γ subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.

Broadening the phenotypic spectrum and physiological insights related toEIF2S3variants

“…The affected sequence is highly conserved at both nucleotide and amino acid levels (Figure ), along with CADD‐score above 20. The p.Met145 residue affected here is located in the GTP‐binding domain of eIF2γ protein (Figure ), just next to a recently reported p.Thr144Ile variant suspect to impair eIF2 function (Kotzaeridou et al, 2020). The c.433A>G, p.(Met145Val) variant has been submitted to NCBI Clinvar database (VCV000804299) (https://www.ncbi.nlm.nih.gov/clinvar/).…”

“…The pathogenicity of p.(Ile465Serfs*4) frameshift variant was obvious due to its recurrence in four unrelated families and to convincing functional studies showing an increase of GCN4 expression in yeast as well as an increased integrated stress response (ISR) in patient‐derived fibroblasts (Skopkova et al, 2017). Regarding missense variants, functional studies with the yeast model confirmed the pathogenicity for five out of six (Borck et al, 2012; Gregory et al, 2019; Kotzaeridou et al, 2020; Skopkova et al, 2017; Young‐Baird et al, 2019). However, it was still unclear how p.(Ser108Arg) missense variant impacts eIF2 function (Skopkova et al, 2017).…”

“…Ten patients from four unrelated families harboring a recurrent frameshift variant p.(Ile465Serfs*4) in EIF2S3 exhibited a severe phenotype of MEHMO syndrome and eight of them died before the age of two (Table ) (Moortgat et al, 2016; Skopkova et al, 2017; Stanik et al, 2018; Steinmuller et al, 1998; Trochanova et al, 2020). Furthermore, 11 patients from 6 unrelated families with missense variants exhibited a less severe and/or mild phenotype (Borck et al, 2012; Gregory et al, 2019; Moortgat et al, 2016; Skopkova et al, 2017) except in one severely affected patient recently reported (Kotzaeridou et al, 2020). Functional assays in yeast have demonstrated that some corresponding variants in the yeast eif2s3 gene impair the binding between the eIF2β and eIF2 γ subunits or between the Met‐tRNA i Met and the eIF2 complex.…”

“…This complex binds to a messenger RNA (mRNA) and starts protein translation. To date, a total of 21 patients from 10 unrelated families have been reported in the literature with pathogenic variants in EIF2S3 (Table ) (Borck et al, 2012; Gregory et al, 2019; Kotzaeridou et al, 2020; Moortgat et al, 2016; Skopkova et al, 2017). Ten patients from four unrelated families harboring a recurrent frameshift variant p.(Ile465Serfs*4) in EIF2S3 exhibited a severe phenotype of MEHMO syndrome and eight of them died before the age of two (Table ) (Moortgat et al, 2016; Skopkova et al, 2017; Stanik et al, 2018; Steinmuller et al, 1998; Trochanova et al, 2020).…”

“…Functional assays in yeast have demonstrated that some corresponding variants in the yeast eif2s3 gene impair the binding between the eIF2β and eIF2 γ subunits or between the Met‐tRNA i Met and the eIF2 complex. The defect of the ternary complex formation increases GCN4 expression, a sensitive reporter of defective eIF2 function in yeast, and leads to decreased accuracy of translation start site selection in vitro and/or in vivo (Borck et al, 2012; Gregory et al, 2019; Kotzaeridou et al, 2020; Skopkova et al, 2017; Young‐Baird et al, 2019). The pathogenicity of p.(Ile465Serfs*4) frameshift variant was obvious due to its recurrence in four unrelated families and to convincing functional studies showing an increase of GCN4 expression in yeast as well as an increased integrated stress response (ISR) in patient‐derived fibroblasts (Skopkova et al, 2017).…”