MEHMO syndrome is a rare X-linked syndrome characterized by Mental retardation, Epilepsy, Hypogenitalism, Microcephaly, and Obesity associated with the defect of protein synthesis caused by the EIF2S3 gene mutations. We hypothesized that the defect in protein synthesis could have an impact on the immune system. We describe immunologic phenotype and possible treatment outcomes in patient with MEHMO syndrome carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. The proband (currently 9-year-old boy) had normal IgG and IgM levels, but had frequent respiratory and urinary tract infections. On subcutaneous immunoglobulin therapy achieving supra-physiological IgG levels the frequency of infections significantly decreased in Poisson regression by 54.5 % (CI 33.2-89.7, p=0.017). The MEHMO patient had had frequent acute infections despite normal IgG and IgM serum levels and responded well to the immunoglobulin treatment.
- MeSH
- dítě MeSH
- epilepsie farmakoterapie genetika imunologie patologie MeSH
- eukaryotický iniciační faktor 2 genetika MeSH
- fenotyp MeSH
- hypogonadismus farmakoterapie genetika imunologie patologie MeSH
- lidé MeSH
- mentální retardace vázaná na chromozom X farmakoterapie genetika imunologie patologie MeSH
- mikrocefalie farmakoterapie genetika imunologie patologie MeSH
- mutace * MeSH
- obezita farmakoterapie genetika imunologie patologie MeSH
- pohlavní orgány abnormality imunologie patologie MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Trypanosomatids regulate gene expression mainly at the post-transcriptional level through processing, exporting and stabilising mRNA and control of translation. In most eukaryotes, protein synthesis is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2) at serine 51. Phosphorylation halts overall translation by decreasing availability of initiator tRNAmet to form translating ribosomes. In trypanosomatids, the N-terminus of eIF2α is extended with threonine 169 the homologous phosphorylated residue. Here, we evaluated whether eIF2α phosphorylation varies during the Trypanosoma cruzi life cycle, the etiological agent of Chagas' disease. Total levels of eIF2α are diminished in infective and non-replicative trypomastigotes compared with proliferative forms from the intestine of the insect vector or amastigotes from mammalian cells, consistent with decreased protein synthesis reported in infective forms. eIF2α phosphorylation increases in proliferative intracellular forms prior to differentiation into trypomastigotes. Parasites overexpressing eIF2αT169A or with an endogenous CRISPR/Cas9-generated eIF2αT169A mutation were created and analysis revealed alterations to the proteome, largely unrelated to the presence of μORF in epimastigotes. eIF2αT169A mutant parasites produced fewer trypomastigotes with lower infectivity than wild type, with increased levels of sialylated mucins and oligomannose glycoproteins, and decreased galactofuranose epitopes and the surface protease GP63 on the cell surface. We conclude that eIF2α expression and phosphorylation levels affect proteins relevant for intracellular progression of T. cruzi.
- MeSH
- buněčné linie MeSH
- Chagasova nemoc parazitologie MeSH
- CRISPR-Cas systémy MeSH
- eukaryotický iniciační faktor 2 genetika metabolismus MeSH
- fosforylace MeSH
- lidé MeSH
- mutace MeSH
- nádorové buněčné linie MeSH
- parazitemie MeSH
- proteom metabolismus MeSH
- proteosyntéza MeSH
- protozoální proteiny analýza biosyntéza metabolismus MeSH
- regulace genové exprese MeSH
- stadia vývoje MeSH
- Trypanosoma cruzi růst a vývoj metabolismus patogenita MeSH
- virulence MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Translational control targeting the initiation phase is central to the regulation of gene expression. Understanding all of its aspects requires substantial technological advancements. Here we modified yeast translation complex profile sequencing (TCP-seq), related to ribosome profiling, and adapted it for mammalian cells. Human TCP-seq, capable of capturing footprints of 40S subunits (40Ss) in addition to 80S ribosomes (80Ss), revealed that mammalian and yeast 40Ss distribute similarly across 5'TRs, indicating considerable evolutionary conservation. We further developed yeast and human selective TCP-seq (Sel-TCP-seq), enabling selection of 40Ss and 80Ss associated with immuno-targeted factors. Sel-TCP-seq demonstrated that eIF2 and eIF3 travel along 5' UTRs with scanning 40Ss to successively dissociate upon AUG recognition; notably, a proportion of eIF3 lingers on during the initial elongation cycles. Highlighting Sel-TCP-seq versatility, we also identified four initiating 48S conformational intermediates, provided novel insights into ATF4 and GCN4 mRNA translational control, and demonstrated co-translational assembly of initiation factor complexes.
- MeSH
- 5' nepřekládaná oblast MeSH
- eukaryotický iniciační faktor 2 genetika metabolismus MeSH
- eukaryotický iniciační faktor 3 genetika metabolismus MeSH
- HEK293 buňky MeSH
- iniciační faktory genetika metabolismus MeSH
- kodon iniciační MeSH
- lidé MeSH
- malé podjednotky ribozomu eukaryotické genetika metabolismus MeSH
- multiproteinové komplexy genetika metabolismus MeSH
- proteosyntéza * MeSH
- ribozomy genetika metabolismus MeSH
- Saccharomyces cerevisiae - proteiny genetika metabolismus MeSH
- Saccharomyces cerevisiae genetika MeSH
- transkripční faktor ATF4 genetika metabolismus MeSH
- transkripční faktory bZIP genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.
- MeSH
- diabetes mellitus 1. typu vrozené genetika MeSH
- endokrinní žlázy metabolismus MeSH
- epilepsie genetika MeSH
- eukaryotický iniciační faktor 2 genetika MeSH
- fenotyp MeSH
- hypoglykemie vrozené genetika MeSH
- hypogonadismus genetika MeSH
- hypopituitarismus vrozené genetika MeSH
- lidé MeSH
- mentální retardace vázaná na chromozom X genetika MeSH
- mikrocefalie genetika MeSH
- novorozenec MeSH
- obezita genetika MeSH
- pohlavní orgány abnormality MeSH
- posunová mutace MeSH
- transkripční faktory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
The integrated stress response is able to rapidly shut down the synthesis of proteins in eukaryotic cells.
