<i>EIF2S3</i>Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO

Škopková, Martina; Hennig, Friederike; Shin, Byung Sik; Turner, Clesson; Staníková, Daniela; Brennerova, Katarina; Staník, Juraj; Fischer, Ute; Henden, Lyndal; Müller, Ulrich; Steinberger, Daniela; Leshinsky‐Silver, Esther; Bottani, Armand; Kurdiová, Tímea; Ukropec, Jozef; Nyitrayova, Olga; Kolníková, Miriam; Klimeš, I; Borck, Guntram; Bahlo, Melanie; Haas, Stefan A.; Kim, Joo Ran; Lotspeich-Cole, Leda E.; Gašperíková, Daniela; Dever, Thomas E.; Kalscheuer, Vera M.

doi:10.1002/humu.23170

Cited by 65 publications

(76 citation statements)

References 77 publications

(111 reference statements)

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“…Because both eIF2 and eIF2B function together in the same pathway and both MEHMO and CACH/VWM likely cause a constitutive reduction in active eIF2 levels, it is surprising that these diseases primarily impact different cell types and have distinct pathologies. However, they do share some overlapping symptoms, as reported in at least some patients (Skopkova et al, 2017). There are some parallels between the tissue-specific effects of both MEHMO and CACH/VWM and the ribosomeopathies, diseases such as Diamond-Blackfan anemia (DBA), where nine different ribosomal proteins are mutated (Boria et al, 2010).…”

Section: Why Do Eif2 and Eif2b Mutations Cause Distinct Pathologies?mentioning

confidence: 98%

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

Pavitt

2018

WIREs RNA

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Phosphorylation of the translation initiation factor eIF2 is one of the most widely used and well-studied mechanisms cells use to respond to diverse cellular stresses. Known as the integrated stress response (ISR), the control pathway uses modulation of protein synthesis to reprogram gene expression and restore homeostasis. Here the current knowledge of the molecular mechanisms of eIF2 activation and its control by phosphorylation at a single-conserved phosphorylation site, serine 51 are discussed with a major focus on the regulatory roles of eIF2B and eIF5 where a current molecular view of ISR control of eIF2B activity is presented. How genetic disorders affect eIF2 or eIF2B is discussed, as are syndromes where excess signaling through the ISR is a component. Finally, studies into the action of recently identified compounds that modulate the ISR in experimental systems are discussed; these suggest that eIF2B is a potential therapeutic target for a wide range of conditions. This article is categorized under: Translation > Translation Regulation.

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Section: Why Do Eif2 and Eif2b Mutations Cause Distinct Pathologies?mentioning

confidence: 98%

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

Pavitt

2018

WIREs RNA

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“…In two additional families, neonatal or young-onset hypoglycemia was reported [50] . A recent study identified EIF2S3 mutations in patients with MEHMO syndrome (mental retardation, epilepsy, hypogonadism and -genitalism, microcephaly, and obesity) [51] . All three patients with this damaging EIF2S3 frameshift mutation who were alive by 1 year developed non-autoimmune insulin-dependent diabetes before that age; in one the presentation was by ketoacidosis.…”

Section: Endoplasmic Reticulum Stress In Monogenic Diabetesmentioning

confidence: 99%

“…In elegant functional studies, Skopkova et al. showed that the frameshift mutation impairs eIF2 function, reducing fidelity of translation start site selection and increasing ATF4 translation and CHOP expression in the ISR [51] ( Figure 3 ).…”

Section: Endoplasmic Reticulum Stress In Monogenic Diabetesmentioning

confidence: 99%

Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

Cnop¹,

Toivonen²,

Igoillo-Esteve³

et al. 2017

Molecular Metabolism

202

179

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BackgroundPancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches.Scope of reviewHere we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells.Major conclusionsPancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.

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“…EIF2B facilitates ternary complex formation and translation initiation through its guanine exchange activity on the eIF2 complex. Dysregulation of eIF2B or other translation factors through mutations or post-translational modifications can contribute to developmental defects, intellectual disability 9 – 11 and neurodegenerative disease 12 – 14 . Moreover, aberrant accumulation of SGs is implicated in the pathogenesis of several neurodegenerative diseases 15 , 16 .…”

Section: Introductionmentioning

confidence: 99%

Analysis of eIF2B bodies and their relationships with stress granules and P-bodies

Moon

Parker

2018

Sci Rep

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Eukaryotic cells respond to stress and changes in the environment in part by repressing translation and forming cytoplasmic assemblies called stress granules and P-bodies, which harbor non-translating mRNAs and proteins. A third, but poorly understood, assembly called the eIF2B body can form and contains the eIF2B complex, an essential guanine exchange factor for the translation initiation factor eIF2. Hypomorphic EIF2B alleles can lead to Vanishing White Matter Disease (VWMD), a leukodystrophy that causes progressive white matter loss. An unexplored question is how eIF2B body formation is controlled and whether VWMD alleles in EIF2B alter the formation of eIF2B bodies, stress granules, or P-bodies. To examine these issues, we assessed eIF2B body, stress granule, and P-body induction in wild-type yeast cells and cells carrying VWMD alleles in the EIF2B2 (GCD7) and EIF2B5 (GCD6) subunits of eIF2B. We demonstrate eIF2B bodies are rapidly and reversibly formed independently of stress granules during acute glucose deprivation. VWMD mutations had diverse effects on stress-induced assemblies with some alleles altering eIF2B bodies, and others leading to increased P-body formation. Moreover, some VWMD-causing mutations in GCD7 caused hyper-sensitivity to chronic GCN2 activation, consistent with VWMD mutations causing hyper-sensitivity to eIF2α phosphorylation and thereby impacting VWMD pathogenesis.

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EIF2S3Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO

Cited by 65 publications

References 77 publications

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

Analysis of eIF2B bodies and their relationships with stress granules and P-bodies

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