scholarly journals Identification of Loss of Function Mutations in Human Genes Encoding RIG-I and MDA5

2009 ◽  
Vol 284 (20) ◽  
pp. 13348-13354 ◽  
Author(s):  
Taeko Shigemoto ◽  
Maiko Kageyama ◽  
Reiko Hirai ◽  
JiPing Zheng ◽  
Mitsutoshi Yoneyama ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Human Genes ◽  
Genes Encoding

scholarly journals Co-expression patterns define epigenetic regulators associated with neurological dysfunction

2018 ◽  
Author(s):  
Leandros Boukas ◽  
James M. Havrilla ◽  
Aaron R. Quinlan ◽  
Hans T. Bjornsson ◽  
Kasper D. Hansen
Keyword(s):  
Expression Patterns ◽  
Neurological Dysfunction ◽  
Dual Function ◽  
Loss Of Function ◽  
Direct Role ◽  
Human Genes ◽  
Systematic Effort ◽  
Genes Encoding ◽  
Epigenetic Regulators ◽  
Coding Variants

AbstractCoding variants in genes encoding for epigenetic regulators are an emerging cause of neurological dysfunction and cancer. However, a systematic effort to identify disease candidates within the human epigenetic machinery (EM) has not been performed, and it is unclear whether features exist that distinguish between variation-intolerant and variation-tolerant EM genes, and between EM genes associated with neurological dysfunction versus cancer. Here, we rigorously define a set of 295 human genes with a direct role in epigenetic regulation (writers, erasers, remodelers, readers). Systematic exploration of these genes reveals that while individual enzymatic functions are always mutually exclusive, readers often also exhibit enzymatic activity as well (dual function EM genes). We find that the majority of EM genes are very intolerant to loss-of-function variation, even when compared to the dosage sensitive group of transcription factors. Using this strategy, we identify 103 novel EM disease candidates. We show that the intolerance to loss-of-function variation is driven by the protein domains encoding the epigenetic function, strongly suggesting that disease is caused by a perturbed chromatin state. Unexpectedly, we also describe a large subset of EM genes that are co-expressed within multiple tissues. This subset is almost exclusively populated by extremely variation-intolerant EM genes, and shows enrichment for dual function EM genes. It is also highly enriched for genes associated with neurological dysfunction, even when accounting for dosage sensitivity, but not for cancer-associated EM genes. These findings prioritize novel disease candidate EM genes, and suggest that the co-expression itself may play a functional role in normal neurological homeostasis.

Identification of microsatellite markers near the human genes encoding the beta-cell ATP-sensitive K+ channel and linkage studies with NIDDM in Japanese

Diabetes ◽  
1996 ◽  
Vol 45 (2) ◽  
pp. 267-269 ◽  
Author(s):  
N. Iwasaki ◽  
M. Kawamura ◽  
K. Yamagata ◽  
N. J. Cox ◽  
S. Karibe ◽  
...  
Keyword(s):  
Beta Cell ◽  
Microsatellite Markers ◽  
K Channel ◽  
Linkage Studies ◽  
Human Genes ◽  
Genes Encoding

scholarly journals Structures and chromosomal localizations of two human genes encoding synaptobrevins 1 and 2.

1990 ◽  
Vol 265 (28) ◽  
pp. 17267-17273 ◽  
Author(s):  
B T Archer ◽  
T Ozçelik ◽  
R Jahn ◽  
U Francke ◽  
T C Südhof
Keyword(s):  
Human Genes ◽  
Genes Encoding

Cloning of Human Genes Encoding Novel G Protein-Coupled Receptors

Genomics ◽  
1994 ◽  
Vol 23 (3) ◽  
pp. 609-618 ◽  
Author(s):  
Adriano Marchese ◽  
John M. Docherty ◽  
Tuan Nguyen ◽  
Michael Heiber ◽  
Regina Cheng ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Human Genes ◽  
Genes Encoding ◽  
G Protein Coupled

scholarly journals act Operon Control of Developmental Gene Expression in Myxococcus xanthus

2002 ◽  
Vol 184 (4) ◽  
pp. 1172-1179 ◽  
Author(s):  
Thomas M. A. Gronewold ◽  
Dale Kaiser
Keyword(s):  
Fruiting Body ◽  
Myxococcus Xanthus ◽  
The Other ◽  
Loss Of Function ◽  
Wild Type ◽  
Developmental Gene ◽  
Developmental Gene Expression ◽  
Mutant Strains ◽  
Genes Encoding ◽  
Signal Production

ABSTRACT Cell-bound C-signal guides the building of a fruiting body and triggers the differentiation of myxospores. Earlier work has shown that transcription of the csgA gene, which encodes the C-signal, is directed by four genes of the act operon. To see how expression of the genes encoding components of the aggregation and sporulation processes depends on C-signaling, mutants with loss-of-function mutations in each of the act genes were investigated. These mutations were found to have no effect on genes that are normally expressed up to 3 h into development and are C-signal independent. Neither the time of first expression nor the rate of expression increase was changed in actA, actB, actC, or actD mutant strains. Also, there was no effect on A-signal production, which normally starts before 3 h. By contrast, the null act mutants have striking defects in C-signal production. These mutations changed the expression of four gene reporters that are related to aggregation and sporulation and are expressed at 6 h or later in development. The actA and actB null mutations substantially decreased the expression of all these reporters. The other act null mutations caused either premature expression to wild-type levels (actC) or delayed expression (actD), which ultimately rose to wild-type levels. The pattern of effects on these reporters shows how the C-signal differentially regulates the steps that together build a fruiting body and differentiate spores within it.

Isolation of Three Novel Human Genes Encoding G Protein-Coupled Receptors

1995 ◽  
Vol 14 (1) ◽  
pp. 25-35 ◽  
Author(s):  
MICHAEL HEIBER ◽  
JOHN M. DOCHERTY ◽  
GIRISH SHAH ◽  
TUAN NGUYEN ◽  
REGINA CHENG ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Human Genes ◽  
Genes Encoding ◽  
G Protein Coupled

scholarly journals CYP2C19 genotype-guided antiplatelet therapy: promises and pitfalls

2020 ◽  
Vol 21 (12) ◽  
pp. 889-897
Author(s):  
Moataz Ellithi ◽  
Jordan Baye ◽  
Russell A Wilke
Keyword(s):  
Cytochromes P450 ◽  
Coronary Intervention ◽  
Antiplatelet Drug ◽  
Major Adverse Cardiovascular Events ◽  
Gene Variants ◽  
Loss Of Function ◽  
Increased Risk ◽  
Percutaneous Coronary ◽  
Genes Encoding ◽  
Cyp2c19 Gene

Pharmacogenetic variants can alter the mechanism of action (pharmacodynamic gene variants) or kinetic processes such as absorption, distribution, metabolism and elimination (pharmacokinetic gene variants). Many initial successes in precision medicine occurred in the context of genes encoding the cytochromes P450 (CYP enzymes). CYP2C19 activates the antiplatelet drug clopidogrel, and polymorphisms in the CYP2C19 gene are known to alter the outcome for patients taking clopidogrel in the context of cardiovascular disease. CYP2C19 loss-of-function alleles are specifically associated with increased risk for coronary stent thrombosis and major adverse cardiovascular events in patients taking clopidogrel following percutaneous coronary intervention. We explore successes and challenges encountered as the clinical and scientific communities advance CYP2C19 genotyping in the context of routine patient care.

scholarly journals Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

2019 ◽  
Vol 8 (2) ◽  
pp. 212 ◽  
Author(s):  
Elena Bacchelli ◽  
Eleonora Loi ◽  
Cinzia Cameli ◽  
Loredana Moi ◽  
Ana Vega Benedetti ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Snp Array ◽  
Anion Channel ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Voltage Dependent Anion Channel ◽  
Multiplex Family ◽  
Genes Encoding ◽  
Additional Support

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.

scholarly journals Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis

2019 ◽  
Vol 78 (5) ◽  
pp. 676-682 ◽  
Author(s):  
Lan Zhao ◽  
Jian Huang ◽  
Yunshan Fan ◽  
Jun Li ◽  
Tianming You ◽  
...  
Keyword(s):  
Structural Damage ◽  
Drug Targets ◽  
Gene Editing ◽  
Joint Damage ◽  
Loss Of Function ◽  
Adeno Associated Virus ◽  
Structural Deterioration ◽  
Efficient Gene ◽  
Genes Encoding ◽  
Surgically Induced

ObjectivesOsteoarthritis (OA) is a painful and debilitating disease and it is associated with aberrant upregulation of multiple factors, including matrix metalloproteinase 13 (MMP13), interleukin-1β (IL-1β) and nerve growth factor (NGF). In this study, we aimed to use the CRISPR/Cas9 technology, a highly efficient gene-editing tool, to study whether the ablation of OA-associated genes has OA-modifying effects.MethodsWe performed intra-articular injection of adeno-associated virus, which expressed CRISPR/Cas9 components to target each of the genes encoding MMP13, IL-1β and NGF, in a surgically induced OA mouse model. We also tested triple ablations of NGF, MMP13 and IL-1β.ResultsLoss-of-function of NGF palliates pain but worsens joint damage in the surgically induced OA model. Ablation of MMP13 or IL-1β reduces the expression of cartilage-degrading enzymes and attenuates structural deterioration. Targeting both MMP13 and IL-1β significantly mitigates the adverse effects of NGF blockade on the joints.ConclusionsCRISPR-mediated ablation of NGF alleviates OA pain, and deletion of MMP13-1β or IL-1β attenuates structural damage in a post-traumatic OA model. Multiplex ablations of NGF, MMP13 and IL-1β provide benefits on both pain management and joint structure maintenance. Our results suggest that CRISPR-based gene editing is useful for the identification of promising drug targets and the development of feasible therapeutic strategies for OA treatment.

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