West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

Alfaiz, Ali Abdullah; Müller, Verena; Boutry‐Kryza, Nadia; Ville, Dorothée; Guex, Nicolas; Bellescize, Julitta de; Rivier, Clotilde; Labalme, Audrey; Portes, Vincent Des; Edery, Patrick; Till, Marianne; Xénarios, Ioannis; Sanlaville, Damien; Herrmann, Johannes M.; Lesca, Gaëtan; Reymond, Alexandre

doi:10.1038/ejhg.2015.227

Cited by 11 publications

(10 citation statements)

References 57 publications

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“…The negative regulation to mRNA binding may belong to the influence of injury created by EP. Translation factor GUF1, mitochondrial (gene name GUF1), may act as a fidelity factor of the translation reaction, by catalyzing a one‐codon backward translocation of tRNAs on improperly translocated ribosomes . It can promote mitochondrial protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Analysis of Cell Responses to Electroporation, a Classical Gene Delivery Approach

Zhao

et al. 2018

Proteomics

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Electroporation, as an established nonviral technology for breaching cell membrane, has been accepted for the delivery of nucleic acids. Despite satisfactory delivery efficiencies have been achieved on multiple cell kinds by simply exhausting all possible electrical parameters, electroporation is still inefficient, or even invalid, for various kinds of cells. This is largely due to the lack of comprehensive understanding of cell responses to electrical stimulation at biological aspect. Moreover, a systematically investigation of protein variation of electroporated cells is also required for biosafety evaluation before clinically applying electroporation. By employing quantitative proteomic analysis, the biological mechanism of electroporation is explored from the molecular level. The results reveal that electrical stimulations widely influence many biological processes including nucleic acid stabilization, protein synthesis, cytoskeleton dynamic, inflammation, and cell apoptosis. It is found that several antivirus-related processes appeared in the enrichment results. Moreover, SAMD9, a broad spectrum antiviral and antitumor factor, is dramatically downregulated on easy-to-transfect cells while electroporation can not alter SAMD9 expression on hard-to-transfect cells, hinting that electroporation, a pure physical treatment, can induce antivirus-like defensive responses and the altering of SAMD9 can be used to predict the effectiveness of electroporation on transfecting specific kinds of cells.

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Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Analysis of Cell Responses to Electroporation, a Classical Gene Delivery Approach

Zhao

et al. 2018

Proteomics

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“…Drosophila waclaw ( waw ) is predicted to have GTP binding activity and GTPase activity. Its human orthologue is the GUF1 gene encoding a mitochondrial elongation factor to regulate the fidelity of translation by catalyzing a one-codon backward translocation of tRNAs on improperly translocated ribosomes [ 162 ]. The GUF1 gene is associated with EIEE ( Table 1 ).…”

Section: Drosophila Epilepsy Modelsmentioning

confidence: 99%

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

Takai

Yamaguchi

Yoshida

et al. 2020

IJMS

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Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use.

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“…There is currently little evidence to support the third variant, rs141526764 (GUF1), having any pathogenic consequences. The association of GUF1 with Mendelian disease (early infantile epileptic encephalopathy) is reported in OMIM as provisional and based solely on the finding of a homozygous missense variant (A609S) in three siblings born to consanguineous parents (37). For all subsequent analyses, we filtered out the two variants considered highly likely not to be LoF (rs760754693, rs10897158), resulting in a final list of 179 predicted LoF variants corresponding to 166 genes ( Table 1).…”

Section: Overlap Of Dispensable Genes With Disease-causing and Essentmentioning

confidence: 99%

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Rausell

Luo

Lopez

et al. 2019

Preprint

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Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups.No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the known FUT2 mutant allele conferring resistance to intestinal viruses and an APOL3 variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes.Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival. Significance statement.Human genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are 3 undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival. 4

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West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

Cited by 11 publications

References 57 publications

Quantitative Proteomic Analysis of Cell Responses to Electroporation, a Classical Gene Delivery Approach

Quantitative Proteomic Analysis of Cell Responses to Electroporation, a Classical Gene Delivery Approach

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

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