scholarly journals Filaggrin gene loss‐of‐function mutations constitute a factor in patients with multiple contact allergies

2019 ◽  
Vol 80 (6) ◽  
pp. 354-358 ◽  
Author(s):  
Youssef Elhaji ◽  
Denis Sasseville ◽  
Melanie Pratt ◽  
Yuka Asai ◽  
Kara Matheson ◽  
...  
Keyword(s):  
Gene Loss ◽  
Loss Of Function

scholarly journals Impact on Bone of an Estrogen Receptor-α Gene Loss of Function Mutation

2008 ◽  
Vol 93 (8) ◽  
pp. 3088-3096 ◽  
Author(s):  
Eric P. Smith ◽  
Bonny Specker ◽  
Bert E. Bachrach ◽  
K. S. Kimbro ◽  
X. J. Li ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Gene Loss ◽  
Estrogen Receptor Α ◽  
Loss Of Function ◽  
Estrogen Receptor Α Gene

PyMut: A Web Tool for Overlapping Gene Loss-of-Function Mutation Design

2018 ◽  
Vol 15 (4) ◽  
pp. 1107-1110 ◽  
Author(s):  
Ke Liu ◽  
Sha Hou ◽  
Junbiao Dai ◽  
Zhirong Sun
Keyword(s):  
Gene Loss ◽  
Loss Of Function ◽  
Web Tool ◽  
Overlapping Gene

scholarly journals Examination of gene loss in the DNA mismatch repair pathway and its mutational consequences in a fungal phylum

2021 ◽  
Author(s):  
Megan A Phillips ◽  
Jacob L Steenwyk ◽  
Xing-Xing Shen ◽  
Antonis Rokas
Keyword(s):  
Powdery Mildew ◽  
Mismatch Repair ◽  
Gene Loss ◽  
Dna Mismatch Repair ◽  
Gc Content ◽  
Mutational Bias ◽  
Sequence Evolution ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mmr Genes

AbstractThe DNA mismatch repair (MMR) pathway corrects mismatched bases produced during DNA replication and is highly conserved across the tree of life, reflecting its fundamental importance for genome integrity. Loss of function in one or a few MMR genes can lead to increased mutation rates and microsatellite instability, as seen in some human cancers. While loss of MMR genes has been documented in the context of human disease and in hypermutant strains of pathogens, examples of entire species and species lineages that have experienced substantial MMR gene loss are lacking. We examined the genomes of 1,107 species in the fungal phylum Ascomycota for the presence of 52 genes known to be involved in the MMR pathway of fungi. We found that the median ascomycete genome contained 49 / 52 MMR genes. In contrast, four closely related species of obligate plant parasites from the powdery mildew genera Erysiphe and Blumeria, have lost between 6 and 22 MMR genes, including MLH3, EXO1, and DPB11. The lost genes span MMR functions, include genes that are conserved in all other ascomycetes, and loss of function of any of these genes alone has been previously linked to increased mutation rate. Consistent with the hypothesis that loss of these genes impairs MMR pathway function, we found that powdery mildew genomes with high levels of MMR gene loss exhibit increased numbers of monomer repeats, longer microsatellites, accelerated sequence evolution, elevated mutational bias in the A|T direction, and decreased GC content. These results identify a striking example of macroevolutionary loss of multiple MMR pathway genes in a eukaryotic lineage, even though the mutational outcomes of these losses appear to resemble those associated with detrimental MMR dysfunction in other organisms.

scholarly journals Promoter CpG density predicts downstream gene loss-of-function intolerance

2020 ◽  
Author(s):  
Leandros Boukas ◽  
Hans T. Bjornsson ◽  
Kasper D. Hansen
Keyword(s):  
Predictive Model ◽  
Gene Loss ◽  
Cpg Islands ◽  
Joint Analysis ◽  
Loss Of Function ◽  
Large Numbers ◽  
Human Genes ◽  
Individual Contributions ◽  
The Individual ◽  
Prevailing View

AbstractThe aggregation and joint analysis of large numbers of exome sequences has recently made it possible to de-rive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF-intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich pro-moters (top 10% CpG density) have a 67.2% probability of being highly LoF-intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.4% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 33.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that out-performs other existing predictors and allows us to classify 1,760 genes – which currently lack reliable LOEUF estimates – as highly LoF-intolerant or not. These predictions have the potential to aid in the interpretation of novel patient variants. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters, but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection.

scholarly journals Paralog dependency indirectly affects the robustness of human cells

2019 ◽  
Author(s):  
Rohan Dandage ◽  
Christian R Landry
Keyword(s):  
Gene Loss ◽  
Fitness Landscape ◽  
Human Cells ◽  
The Other ◽  
Gene Copy ◽  
Deleterious Mutations ◽  
Loss Of Function ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
Paralogous Proteins

SummaryGene duplicates provide protection against loss-of-function mutations. This protective redundancy partly relies on the fact that paralogs carry their functions independently, i.e. the inactivation of one gene copy does not impair the function of the other copy. However, a significant fraction of paralogous proteins may form functionally dependent pairs, for instance through heteromerization. As a consequence, one could expect these heteromeric paralogs to be less protective against deleterious mutations. To test this hypothesis, we examined the fitness landscape of gene loss-of-function by CRISPR-Cas9 in more than 450 human cell lines. Our analysis revealed a robustness landscape of human cells showing regions of higher vulnerability to gene inactivation as a function of key paralog properties. We find that heteromerizing paralogs are indeed less protective than non-heteromeric ones, but this association is largely due to their higher abundance and their larger number of protein-protein interaction partners.

scholarly journals Implication of folate deficiency in CYP2U1 loss of function

2021 ◽  
Vol 218 (11) ◽  
Author(s):  
Claire Pujol ◽  
Anne Legrand ◽  
Livia Parodi ◽  
Priscilla Thomas ◽  
Fanny Mochel ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorders ◽  
Gene Loss ◽  
Coenzyme Q ◽  
Complex Form ◽  
Loss Of Function ◽  
Folate Supplementation ◽  
Hereditary Spastic Paraplegias ◽  
Neurodegenerative Process ◽  
Potential Biomarker

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

Gene Loss-of-Function and Live Imaging in Chick Embryos

2011 ◽  
pp. 105-117 ◽  
Author(s):  
Anne C. Rios ◽  
Christophe Marcelle ◽  
Olivier Serralbo
Keyword(s):  
Gene Loss ◽  
Live Imaging ◽  
Chick Embryos ◽  
Loss Of Function

scholarly journals GUCY2D Gene Loss-of-Function Mutations Responsible for Leber Congenital Amaurosis 1

2019 ◽  
Author(s):  
Feng Xue ◽  
Tianying Wei ◽  
Junhui Sun ◽  
Yuqin Luo ◽  
Yanan Huo ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Guanylate Cyclase ◽  
Gene Loss ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Loss Of Function ◽  
Wild Type ◽  
Leber Congenital Amaurosis ◽  
Cellular Location ◽  
Generation Sequencing

Abstract Background: Leber congenital amaurosis (LCA) is a group of severe congenital neurodegenerative diseases. Variants in the guanylate cyclase 2D gene ( GUCY2D ), which encodes guanylate cyclase 1 (ROS-GC1), are associated with LCA1 and account for 6%–21% of all LCA cases. Methods: In this study, one family with LCA1 was recruited from China. A combination of next generation sequencing and Sanger sequencing was used to screen for disease-causing mutations. Additionally, immunohistochemistry and HPLC-coupled tandem mass spectrometry (HPLC-MS/MS) were used to confirm the cellular location and catalytic activity of ROS-GC1 mutants, respectively. Results: We found three novel mutations (c.139_139delC, c.835G>A and c.2783G>A) in the GUCY2D gene. Mutation c.139_139delC results in a truncated protein. Mutations c.835G>A and c.2783G>A exert no effects on cellular location but reduce significantly the catalytic activity of ROS-GC1. Conclusions: Our findings highlight the clinical range of LCA. Moreover, HPLC-MS/MS was used to analyze the concentration of 3',5'-cyclic guanosine monophosphate (cGMP), suggesting that HPLC-MS/MS is an effective alternative method to evaluate the catalytic activity of wild-type and mutant ROS-GC1 Keywords: Leber congenital amaurosis 1, GUCY2D , catalytic activity, 3',5'-cyclic guanosine monophosphate, guanylate cyclase 1

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