scholarly journals PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations

Oncogene ◽  
2013 ◽  
Vol 33 (20) ◽  
pp. 2568-2576 ◽  
Author(s):  
A I Velghe ◽  
S Van Cauwenberghe ◽  
A A Polyansky ◽  
D Chand ◽  
C P Montano-Almendras ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Gain Of Function ◽  
Passenger Mutations

scholarly journals Genetic and Molecular Characterization of the Caenorhabditis elegans Gene, mel-26, a Postmeiotic Negative Regulator of MEI-1, a Meiotic-Specific Spindle Component

Genetics ◽  
1998 ◽  
Vol 150 (1) ◽  
pp. 119-128
Author(s):  
M Rhys Dow ◽  
Paul E Mains
Keyword(s):  
Caenorhabditis Elegans ◽  
Protein Interactions ◽  
Negative Regulator ◽  
Meiotic Spindle ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Gain Of Function ◽  
Recessive Mutations ◽  
Female Germline

Abstract We have previously described the gene mei-1, which encodes an essential component of the Caenorhabditis elegans meiotic spindle. When ectopically expressed after the completion of meiosis, mei-1 protein disrupts the function of the mitotic cleavage spindles. In this article, we describe the cloning and the further genetic characterization of mel-26, a postmeiotic negative regulator of mei-1. mel-26 was originally identified by a gain-of-function mutation. We have reverted this mutation to a loss-of-function allele, which has recessive phenotypes identical to the dominant defects of its gain-of-function parent. Both the dominant and recessive mutations of mel-26 result in mei-1 protein ectopically localized in mitotic spindles and centrosomes, leading to small and misoriented cleavage spindles. The loss-of-function mutation was used to clone mel-26 by transformation rescue. As suggested by genetic results indicating that mel-26 is required only maternally, mel-26 mRNA was expressed predominantly in the female germline. The gene encodes a protein that includes the BTB motif, which is thought to play a role in protein-protein interactions.

scholarly journals Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 374
Author(s):  
Oscar Brenes ◽  
Raffaella Barbieri ◽  
Melissa Vásquez ◽  
Rebeca Vindas-Smith ◽  
Jeffrey Roig ◽  
...  
Keyword(s):  
Structural Damage ◽  
Novel Mutation ◽  
Loss Of Function ◽  
Strong Decrease ◽  
Unrelated Family ◽  
Gain Of Function ◽  
Recovery From Inactivation ◽  
Steady State Inactivation ◽  
Voltage Sensor Domain

Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen’s disease. One novel mutation (p.W322*) in CLCN1 and one undescribed mutation (p.R1463H) in SCN4A are segregating in this family. The CLCN1-p.W322* was also found in an unrelated family, in compound heterozygosity with the known CLCN1-p.G355R mutation. One reported mutation, SCN4A-p.T1313M, was found in a third family. Both CLCN1 mutations exhibited loss-of-function: CLCN1-p.W322* probably leads to a non-viable truncated protein; for CLCN1-p.G355R, we predict structural damage, triggering important steric clashes. The SCN4A-p.R1463H produced a positive shift in the steady-state inactivation increasing window currents and a faster recovery from inactivation. These gain-of-function effects are probably due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD) IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that CLCN1-p.W322* and SCN4A-p.R1463H mutations can act alone or in combination as inducers of myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to provide accurate genetic counseling and management of patients.

scholarly journals Functional Characterization of KCNMA1 mutation associated with dyskinesia, seizure, developmental delay, and cerebellar atrophy

2021 ◽  
Author(s):  
Emrah Yucesan ◽  
Beyza Goncu ◽  
Cemil Ozgul ◽  
Arda Kebapci ◽  
Ayca Dilruba Aslanger ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Cerebellar Atrophy ◽  
Bk Channels ◽  
Bk Channel ◽  
Functional Study ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Α Subunit ◽  
Truncating Mutation

Abstract KCNMA1 located on chromosome 10q22.3, encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K + channel. BK channels are widely distributed across tissues, including both excitable and non excitable cells. Numerous evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with different symptoms, such as paroxysmal non kinesigenic dyskinesia with gain of function and ataxia with loss of function. Functional classifications revealed two major patterns, gain of function and loss of function effects on channel properties in different cell lines. In the literature, two mutations have been shown to confer gain of function properties to BK channels: D434G and N995S. On the other hand 10 mutations have been classified as loss of function (S351Y,G354S, G356R, G375R, C413Y/N449fs, I663V, P805L, and D984N) or putative loss of function (premature truncation mutations: Y676Lfs*7 and Arg458Ter). In this study, we report the functional characterization of a variant which was previously reported the whole exome sequencing revealed bi-allelic nonsense variation (NM_001161352.1 (ENST00000286628.8):c.1372C > T; Arg458*) of the cytoplasmic domain of calcium-activated potassium channel subunit alpha-1 protein. To detect functional consequences of the variation immunostaining and electrophysiological studies were conducted. In this study, we conducted patch-clamp recordings on WT and R458X mutant cells. We found the gain of function effect for the mutation. This is the first functional study observing an increased current in the KCNMA1 gene resulting from a truncating mutation

scholarly journals Molecular genetics of the Posterior sex combs/Suppressor 2 of zeste region of Drosophila: aberrant expression of the Suppressor 2 of zeste gene results in abnormal bristle development.

Genetics ◽  
1991 ◽  
Vol 128 (1) ◽  
pp. 119-132
Author(s):  
B P Brunk ◽  
E C Martin ◽  
P N Adler
Keyword(s):  
Dna Sequences ◽  
Polycomb Group ◽  
Loss Of Function ◽  
Distal Breakpoint ◽  
Gain Of Function ◽  
Aberrant Expression ◽  
Sex Combs ◽  
Foreign Dna

Abstract We report the molecular characterization of the Posterior sex combs-Suppressor 2 of zeste region of Drosophila melanogaster. The distal breakpoint of the Aristapedioid inversion divides the region into two parts. We have molecularly mapped the lesions associated with several loss of function mutations in the Polycomb group gene Posterior sex combs (Psc) proximal to this breakpoint. In addition, we have found that lesions associated with several loss of function mutations in the Suppressor 2 of zeste [Su(z)2] gene lie distal to this breakpoint. Since the breakpoint does not cause a loss of function in either gene, no essential sequences are shared by these two neighboring genes. There are three dominant gain of function mutations in the region that result in abnormal bristle development. We find that all three juxtapose foreign DNA sequences upstream of the Su(z)2 gene, and that at least two of these mutations (Arp1 and vgD) behave genetically as gain of function mutations in Su(z)2. Northern and in situ hybridization analyses show that the mutations result in increased accumulation of the Su(z)2 mRNA, which we argue is responsible for the bristle loss phenotype.

A screen for suppressors of apoptosis identifies a novel gain of function mutation in drosphilia RAS1s

2007 ◽  
Vol 30 (4) ◽  
pp. 82
Author(s):  
C Gafuik ◽  
J Agapite ◽  
H Steller
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Model Organisms ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Ras Oncogenes ◽  
Induced Apoptosis

Background: Apoptosis is a morphologically distinct, genetically programmed form of cell death that is evolutionarily highly conserved amongst multi-cellular eukaryotes. Correct regulation of apoptosis is critical for normal development and the prevention of diseases, such as cancer. Genetic analysis of invertebrate model organisms has proven invaluable for the identification and study of key molecules involved in apoptosis. In Drosophila, the proteins Reaper (Rpr), Head involution defective (Hid) and Grim induce cell death in a caspase dependent manner by inhibiting the anti-apoptotic function of diap1. Methods: To further elucidate the molecular mechanisms underlying the control of apoptosis, we conducted a dominant modifier screen for genes that could suppress the strong eye ablation phenotype caused by expressing hid under the control of an eye-specific promoter. Results: As previously reported, we identified several loss of function mutants in components of the EGFR/Ras/MAPK pathway that could dominantly suppress hid-induced apoptosis. These mutants proved to be alleles of either sprouty or gap1, two negative regulators of the RTK/Ras1 signaling. Here we report the identification and characterization of the first gain of function mutation in the Drosophila RAS1 gene. Conclusions: Taken together, these findings provide a molecular paradigm for the anti-apoptotic function of ras oncogenes.

scholarly journals Discovery and functional characterization of a neomorphic PTEN mutation

2015 ◽  
Vol 112 (45) ◽  
pp. 13976-13981 ◽  
Author(s):  
Helio A. Costa ◽  
Michael G. Leitner ◽  
Martin L. Sos ◽  
Angeliki Mavrantoni ◽  
Anna Rychkova ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Functional Characterization ◽  
Genetic Alterations ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Phosphatase And Tensin Homolog ◽  
Pten Loss ◽  
Tensin Homolog ◽  
Cancer Tumor

Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.

scholarly journals Characterization of a new mouse p53 variant: loss-of-function and gain-of-function

2014 ◽  
Vol 21 (1) ◽  
pp. 40 ◽  
Author(s):  
James Yi-Hsin Chan ◽  
Ying-Chuan Chen ◽  
Shu-Ting Liu ◽  
Wei-Yuan Chou ◽  
Ching-Liang Ho ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Gain Of Function
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