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At least 19 recordsLinked to original sources
PubMed2026

A new MRR1 gain-of-function mutation involved in cross-resistance to antifungal agents in the fungal priority pathogen Candida parapsilosis.

OBJECTIVES: Candida parapsilosis is a leading cause of invasive candidiasis globally, with rising reports of fluconazole resistance threatening its clinical management. Among the mechanisms involved, gain-of-function mutations in the MRR1 gene have emerged as key drivers of antifungal resistance. We aimed to investigate a novel amino acid substitution (G982E) in the Mrr1 zinc cluster transcription factor, identified in a fluconazole-resistant C. parapsilosis isolate from a patient exposed to fluconazole. METHODS: Using CRISPR-Cas9 genome editing, we introduced the G982E variant into two fluconazole-susceptible C. parapsilosis genetic backgrounds. The antifungal susceptibility of the engineered mutants was assessed in vitro against a broad panel of systemic antifungal agents. A Galleria mellonella infection model was also used to evaluate the impact of the G982E variant on antifungal treatment efficacy and virulence in vivo. RESULTS: Acquisition of the G982E substitution dramatically altered the antifungal susceptibility profile, particularly for fluconazole for which the MIC increased to >256 µg/mL. However, the magnitude of the MIC increase varied by azole, with the greatest increase seen for fluconazole (>9-10-fold), followed by voriconazole (5-fold), isavuconazole (3-fold), but also flucytosine (1.5-fold). In contrast, susceptibility to posaconazole remained largely unchanged. In vivo, this new variant conferred fluconazole treatment failure but was associated with a significant reduction in virulence. CONCLUSIONS: The G982E is a novel Mrr1 gain-of-function mutation driving high-level fluconazole resistance in C. parapsilosis. These findings reinforce the central role of Mrr1 in antifungal resistance, underscore the functional diversity of its mutational landscape, with potential implications for fungal fitness and transcriptional regulation.

Candida parapsilosis↗
PubMed1990

Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans.

Certain cell fate decisions are specified by cell-cell interactions during the development of the nematode Caenorhabditis elegans. For example, in a wild-type hermaphrodite gonad, two cells, Z1.ppp and Z4.aaa, have the potential to become the anchor cell (AC). Intercellular communication establishes their fates and ensures that only one cell becomes the AC, while the other becomes a ventral uterine precursor cell (VU). One component of this intercellular communication seems to be the 'AC-to-VU' signal from the presumptive AC that causes the other cell to become a VU. Genetic and developmental studies indicated that the lin-12 gene specifies the fates of Z1.ppp and Z4.aaa. Molecular studies suggest that lin-12 directly participates in their communications, perhaps acting as the receptor for the 'AC-to-VU' signal. Here, we report the molecular lesions associated with lin-12 gain-of-function mutations, cell isolation experiments, and genetic studies of an unusual lin-12 allele. These data suggest that self-association of the putative lin-12-encoded receptor leads to its activation, and that certain gain-of-function mutations result in ligand-independent activation.

Alleles↗
PubMed1987

Gain-of-function mutations of fem-3, a sex-determination gene in Caenorhabditis elegans.

We have isolated nine gain-of-function (gf) alleles of the sex-determination gene fem-3 as suppressors of feminizing mutations in fem-1 and fem-2. The wild-type fem-3 gene is needed for spermatogenesis in XX self-fertilizing hermaphrodites and for male development in both soma and germ line of XO animals. Loss-of-function alleles of fem-3 transform XX and XO animals into females (spermless hermaphrodites). In contrast, fem-3(gf) alleles masculinize only one tissue, the hermaphrodite germ line. Thus, XX fem-3(gf) mutant animals have a normal hermaphrodite soma, but the germ line produces a vast excess of sperm and no oocytes. All nine fem-3(gf) alleles are temperature sensitive. The temperature-sensitive period is from late L4 to early adult, a period just preceding the first signs of oogenesis. The finding of gain-of-function alleles which confer a phenotype opposite to that of loss-of-function alleles supports the idea that fem-3 plays a critical role in germ-line sex determination. Furthermore, the germ-line specificity of the fem-3(gf) mutant phenotype and the late temperature-sensitive period suggest that, in the wild-type XX hermaphrodite, fem-3 is negatively regulated so that the hermaphrodite stops making sperm and starts making oocytes. Temperature shift experiments also show that, in the germ line, sexual commitment appears to be a continuing process. Spermatogenesis can resume even after oogenesis has begun, and oogenesis can be initiated much later than normal.

Alleles↗
PubMed1990

Aristapedioid: a gain of function, homeotic mutation in Drosophila melanogaster.

The isolation of gain of function mutations has allowed the identification of a number of genes which are important in the normal development of the organism. We report here the isolation and characterization of Aristapedioid, a gain of function mutation which causes a partial transformation of arista towards tarsus and the loss or decrease in size of the dorso-central and scutellar bristles. Aristapedioid is the result of a P element mediated inversion which juxtaposes unrelated DNA adjacent to Suppressor 2 of zeste, causing a gain of function mutation in that gene.

Alleles↗
PubMed1991

Dominant gain-of-function mutations that lead to misregulation of the C. elegans heterochronic gene lin-14, and the evolutionary implications of dominant mutations in pattern-formation genes.

The heterochronic gene lin-14 controls the temporal sequence of developmental events in the C. elegans postembryonic cell lineage. It encodes a nuclear protein that is normally present in most somatic cells of late embryos and L1 larvae but not in later larval stages or adults. Two lin-14 gain-of-function mutations cause an inappropriately high level of the lin-14 nuclear protein late in development. These mutations delete 3' untranslated sequences from the lin-14 mRNAs and identify a negative regulatory element that controls the formation of the lin-14 protein temporal gradient. The 21 kb lin-14 gene contains 13 exons that are differentially spliced to generate two lin-14 protein products with variable N-terminal regions and a constant C-terminal region. No protein sequence similarity to any proteins in various databases was found. The temporal and cellular expression patterns of lin-14 protein accumulation is altered by mutations in the heterochronic genes lin-4 and lin-28. The lin-4 gene is required to down-regulate lin-14 protein levels during the mid-L1 stage. The lin-4 gene product could be the trans-acting factor that binds to the negative regulatory element in the lin-14 3' untranslated region. In contrast, the lin-28 gene activity positively regulates lin-14 protein levels during early L1. Thus, these genes act antagonistically to regulate the lin-14 temporal switch. The normal down-regulation of lin-14 within 10 h of hatching is not determined by the passage of time per se, but rather is triggered when feeding induces post-embryonic development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2025

Clinical and electrophysiological characterization of a SCN5A gain-of-function mutation associated with CPVT-like arrhythmia.

The present study aimed to characterize the SCN5A variant I1333V, found in five families with a history of suspected catecholaminergic polymorphic ventricular tachycardia (CPVT). SCN5A encodes the pore-forming subunit of the cardiac voltage-gated sodium channel NaV1.5. Gain of SCN5A function causes long QT syndrome type 3 (LQT3), but its involvement in CPVT is disputed. Nineteen patients harboring the I1333V variant were identified across five families, commonly presenting with exercise-induced arrhythmia, including polymorphic premature ventricular contractions, ventricular bigeminy, couplets, and ventricular tachycardias. Prolonged QT interval was a less consistent finding, and structural myocardial changes were absent. Human NaV1.5/β1 complexes were expressed in Xenopus laevis oocytes, using RNA combinations to emulate homozygous wild-type, heterozygous and homozygous I1333V-mutant conditions. Cells were studied using the cut-open oocyte Vaseline gap voltage-clamp to evaluate effects of I1333V on NaV1.5 function. NaV1.5(I1333V) channels required less depolarization to activate, classifying this variant as gain-of-function. Fast inactivation was unaffected, and action-potential (AP) clamp showed no significant differences in late Na+ current. A computational model of human ventricular myocyte excitability predicted no effect of I1333V on AP duration; instead, it showed stronger Na+ influx during the AP upstroke, concurrent with elevated Ca2+ import via the sodium‑calcium exchanger. Finally, NaV1.5(I1333V) channels exhibited a diminished response to cAMP (emulating adrenergic stimulation), which also likely contributes to arrhythmogenesis. In conclusion, I1333V is a gain-of-function variant of SCN5A with a unique set of functional consequences. It is associated with cardiac arrhythmia disease characterized by overlapping CPVT-like and LQT3 features. Our findings support that SCN5A should be considered in genetic screening of suspected CPVT.

NAV1.5 Voltage-Gated Sodium Channel↗
PubMed1992

Characterization of a gain of function mutation of integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa).

Integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) is a prototype of integrins involved in cellular adhesive functions. As part of a structure-function analysis of this molecule, we constructed a mutant, designated alpha IIb beta 3 (beta 1-2), by replacing 6 amino acids within a putative ligand binding domain of the beta 3 subunit with sequences derived from beta 1. The alteration did not affect the capacity of beta 3(beta 1-2) to combine with transfected alpha IIb, nor did it cause it to combine with endogenous alpha 5. Integrin alpha IIb beta 3(beta 1-2) was in a "resting" state on Chinese hamster ovary cells as judged by minimal binding of an activation-specific anti-alpha IIb beta 3, PAC1. Nevertheless, cells expressing alpha IIb beta 3(beta 1-2) spontaneously bound fibrinogen with low affinity (Ka = (4.85 +/- 0.84) x 10(6) M-1). Activation with an anti-beta 3 antibody (monoclonal antibody 62) resulted in a 10-fold increase in fibrinogen binding affinity (Ka = (4.55 +/- 0.77) x 10(7) M-1), which was 3-fold greater than fibrinogen binding to activated wild type alpha IIb beta 3 (Ka = (1.66 +/- 0.33) x 10(7) M-1, F = 7.46, p = 0.008). The mutant receptor also bound fibrinogen mimetic peptide ligands with enhanced affinity as measured by the conformation-specific antibody, anti-LIBS1. This indicates that the increased affinity for fibrinogen was caused by enhanced interaction of alpha IIb beta 3(beta 1-2) with known recognition sequences in fibrinogen. Thus, this gain of function mutant augments ligand binding function, supporting a role for this region of the beta subunit in ligand binding to integrins.

Amino Acid Sequence↗
PubMed2025

Gain-of-function PPM1D mutations attenuate ischemic stroke.

Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene. Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d-/-) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d-/- mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke. Gain-of-function PPM1D mutations attenuate ischemic cerebral injury. Whole-genome sequencing data of 10,241 ischemic stroke patients from the Third Chinese National Stroke Registry (CNSR-III) identified eight patients with gain-of-function mutations in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene (17q23.2). These mutation carriers displayed improved peripheral inflammation, decreased fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Ppm1d-deficient (Ppm1d-/-) mice exhibited exacerbated stroke outcomes, characterized by enlarged infarct volumes, disrupted cerebrovascular architecture, and enhanced neuro-inflammation. Mechanistically, Ppm1d deficiency induced the disturbance of endothelial fatty acid metabolism involving the PPARα pathway. Through integrated computational modeling, virtual screening, and in vitro validation, T2755 was identified as a small molecule PPM1D stabilizer. Pharmacological PPM1D stabilization with T2755 significantly attenuated ischemic brain injury in murine models.

Aged↗
PubMed1992

Disorganization is a completely dominant gain-of-function mouse mutation causing sporadic developmental defects.

Disorganization (Ds) is an exceptional mutation because of its diverse and profound developmental effects. Although other mouse mutations produce similar congenital defects, extreme pleiotropism, random occurrence, developmental independence of multiple defects, and type of anomaly make Ds unique. Examples of developmental defects include cranioschisis, rachischisis, thoracoschisis, exencephaly, hamartomas, and anomalies of appendages, digestive, genital and urinary tracts, sense organs, limbs and girdles, tail and pharynx. No other mutation in the mouse has such broad effects. Ds is therefore an important model for studying not only the genetic control of lineage determination and pattern formation, but also the occurrence of sporadic congenital defects. To characterize the effects of gene dosage, we examined the viability and phenotype of Ds homozygotes and the phenotype of +/+/Ds trisomic fetuses. Occurrence of homozygotes was tested by intercrossing Ds/+ heterozygotes, typing genetic markers that flank Ds, and examining homozygotes for morphological abnormalities. Not only were Ds homozygotes found in their expected frequency, homozygotes were not more severely affected than heterozygotes. Trisomies provide a direct test for determining whether Ds is a gain-of-function mutation. Trisomic fetuses were derived by crossing Ds/Ds homozygous mice to hybrid mice that were heterozygous for two related Robertsonian translocations. Two trisomic fetuses had developmental defects characteristic of Ds mice. Together these results demonstrate that Ds is a completely dominant, gain-of-function mutation.

Abnormalities, Multiple↗
PubMed1992

cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function.

We report the expression cloning of pMev, a cDNA that facilitates cellular uptake of mevalonate. pMev was isolated from the met-18b-2 clone of Chinese hamster ovary (CHO) cells, which were selected for growth in low concentrations of mevalonate when synthesis is blocked by compactin (Faust, J. R., and Krieger, M. (1987) J. Biol. Chem. 262, 1996-2004). pMev encodes a 494-residue protein, Mev, that is predicted to have 12 membrane-spanning regions, consistent with a membrane transporter. Surprisingly, levels of Mev mRNA and protein are similar in CHO and met-18b-2 cells. The Mev gene differs from the wild-type gene by a single base change that substitutes a cysteine for phenylalanine in the 10th membrane-spanning region. met-18b-2 cells are heterozygous for this dominant gain-of-function mutation. Transfection of a cDNA encoding pMev, but not the wild-type cDNA, elicited a marked increase in [3H]mevalonate uptake and incorporation into cellular lipids in stably and transiently transfected cells. The availability of pMev will facilitate studies of [3H]mevalonate incorporation into trace products, including p21ras and other prenylated proteins.

Amino Acid Sequence↗
PubMed1990

The let-60 locus controls the switch between vulval and nonvulval cell fates in Caenorhabditis elegans.

During induction of the Caenorhabditis elegans hermaphrodite vulva by the anchor cell of the gonad, six multipotent vulval precursor cells (VPCs) have two distinct fates: three VPCs generate the vulva and the other three VPCs generate nonspecialized hypodermis. Genes that control the fates of the VPCs in response to the anchor cell signal are defined by mutations that cause all six VPCs to generate vulval tissue (Multivulva or Muv) or that cause all six VPCs to generate hypodermis (Vulvaless or Vul). Seven dominant Vul mutations were isolated as dominant suppressors of a lin-15 Muv mutation. These mutations are dominant alleles of the gene let-60, previously identified only by recessive lethal mutations. Our genetic studies of these dominant Vul recessive lethal mutations, recessive lethal mutations, intragenic revertants of the dominant Vul mutations, and the closely mapping semi-dominant multivulva lin-34 mutations suggest that: (1) loss-of-function mutations of let-60 are recessive lethal at a larval stage, but they also cause a Vul phenotype if the lethality is rescued maternally by a lin-34 gain-of-function mutation. (2) The dominant Vul alleles of let-60 are dominant negative mutations whose gene products compete with wild-type activity. (3) lin-34 semidominant Muv alleles are either gain-of-function mutations of let-60 or gain-of-function mutations of an intimately related gene that elevates let-60 activity. We propose that let-60 activity controls VPC fates. In a wild-type animal, reception by a VPC of inductive signal activates let-60, and it generates into a vulval cell type; in absence of inductive signal, let-60 activity is low and the VPC generates hypodermal cells. Our genetic interaction studies suggest that let-60 acts downstream of let-23 and lin-15 and upstream of lin-1 and lin-12 in the genetic pathway specifying the switch between vulval and nonvulval cell types.

Alleles↗
PubMed1991

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.

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.

Animals↗
PubMed1989

Genetic interactions of the suppressor 2 of zeste region genes.

A wide variety of gain of function mutations have been induced in the Posterior Sex Comb (Psc)--Aristapedioid (Arp)--Suppressor 2 of zeste (Su(z)2) region of the second chromosome of Drosophila. This region contains at least three apparently related genes, two of which we have been studying. Psc1 has previously been used to identify Psc as a Pc group gene; however, it is a complex mutation with both gain and loss of function character. We report here that the Pc group character of Psc is not due to a gain of function and presumably reflects the function of the wild-type gene. We also provide evidence for a maternal function for Psc, as well as the neighboring Su(z)2 gene. Su(z)2 does not appear to be a Pc group gene as it does not act in a synergistic fashion with other Pc group genes in promoting posteriorly directed transformations. However, we have found that mutations in Su(z)2 do interact in a variety of interesting ways with mutations in Pc group genes.

Alleles↗
PubMed1991

napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription.

napts is a recessive mutation that affects the level of sodium channel activity and, at high temperature, causes paralysis associated with a loss of action potentials. We show, by genetic complementation tests, germline transformation, and analysis of mutations, that napts is a gain-of-function mutation of mle, a gene required for X chromosome dosage compensation and male viability. Molecular analyses of nap and mle mutations indicate that mle+, nap+, and napts activities are encoded by the same open reading frame and suggest that napts is due to a single amino acid substitution. Although napts is known to act via para+, an X-linked sodium channel structural gene, its effect is not due to a simple defect in para+ dosage compensation.

Action Potentials↗
PubMed1986

Dominant maternal-effect mutations of Drosophila melanogaster causing the production of double-abdomen embryos.

Dominant mutations at two loci, BicaudalC (BicC) and BicaudalD (BicD), cause heterozygous females to produce double-abdomen embryos. These mutations cause the production of embryos with a range of defects extending from the anterior end of the differentiated embryo. The same array of defective embryos is caused by mutations at either locus and is similar to that produced by the original mutation at bicaudal (bic). The array of defective embryos suggests that these mutations cause the loss of positional values from the anterior end of the embryo, associated with a duplication of the posterior end if too few positional values remain. BicaudalD mutations appear to be antimorphic, gain-of-function mutations, whereas BicaudalC mutations are likely to be hypomorphic or amorphic mutations. Mutations at all these loci (bic, BicC and BicD) act as mutual enhancers of each other, and a number of other maternal-effect mutations also act to either enhance or suppress the expression of these dominant bicaudal mutations.

Abdomen↗
PubMed1992

Enhanced export of beta-galactosidase fusion proteins in prlF mutants is Lon dependent.

We have used fusions of the outer membrane protein LamB to beta-galactosidase (encoded by lacZ) to study the protein export process. This LamB-LacZ hybrid protein blocks export when synthesized at high levels, as evidenced by inducer (maltose) sensitivity, a phenomenon termed LacZ hybrid jamming. The prlF1 mutation relieves LacZ hybrid jamming and allows localization of the fusion protein to a noncytoplasmic compartment. prlF1 and similar alleles are gain-of-function mutations. Null mutations in this gene confer no obvious phenotypes. Extragenic suppressors of a gain-of-function prlF allele have been isolated in order to understand how this gene product affects the export process. The suppressors are all lon null mutations, and they are epistatic to all prlF phenotypes tested. Lon protease activity has been measured in prlF1 cells and shown to be increased. However, the synthesis of Lon is not increased in a prlF1 background, suggesting a previously unidentified mechanism of Lon activation. Further analysis reveals that prlF1 activates degradation of cytoplasmically localized precursors in a Lon protease-dependent manner. It is proposed that accumulation of precursors during conditions of hybrid protein jamming titrates an essential export component(s), possibly a chaperone. Increased Lon-dependent precursor degradation would free this component, thus allowing increased protein export under jamming conditions.

ATP-Dependent Proteases↗
PubMed1992

Localization of DER and the pattern of cell divisions in wild-type and Ellipse eye imaginal discs.

The compound eye of Drosophila develops from a uniform layer of epithelial cells in the eye imaginal disc. One intriguing aspect of eye development is the establishment of the correct number and spacing of the photoreceptor clusters which give rise to the mature ommatidia. Ellipse (Elp) has been implicated as playing a role in this process because the Elp dominant gain of function mutation dramatically reduces the number of photoreceptor clusters in the compound eye without affecting the morphology of individual clusters that are formed (Baker and Rubin, 1989). Since Elp represents an allele of the Drosophila EGF receptor (DER) locus, it encodes a protein which is structurally capable of mediating inductive cell-cell interactions. In an effort to better understand the role of the DER locus in ommatidial patterning, we compared the localization of DER protein in eye imaginal discs of wild-type and Elp larvae. The distribution of this receptor is consistent with the notion of its mediating interactions between cells at the initial stages of photoreceptor precluster positioning and differentiation. However, the basis of the Elp gain of function mutation is not ectopic or increased expression of the DER protein. Rather, expression of the Elp form of the EGF receptor homolog in the normal localization leads to changes in the proliferative pattern of cells dividing posterior to the morphogenetic furrow.

Animals↗
PubMed1989

The role of easter, an apparent serine protease, in organizing the dorsal-ventral pattern of the Drosophila embryo.

The maternally transcribed product of the Drosophila easter gene is essential for the establishment of a normal dorsal-ventral pattern in embryos. Loss-of-function mutations in easter result in a dorsalization of the embryonic pattern, while dominant gain-of-function mutations ventralize the embryonic pattern. P element insertion alleles of easter were isolated and used to identify genomic and cDNA clones that include the easter gene. Injection of in vitro-synthesized transcripts of the cDNA into embryos from easter mutant females completely rescued the mutant phenotype, allowing normal development. This result confirmed that the cDNA encodes easter and that the easter product is only required after fertilization. The sequence of the cDNA suggests that the product of the easter gene is an extracytoplasmic serine protease. The implications of the dominant alleles of this putative protease for the mechanism of dorsal-ventral pattern formation are discussed.

Alleles↗