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Results for “Gain of Function Mutation”

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PubMed2003

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

Animals↗
PubMed2005

CXCR4 mutations in WHIM syndrome: a misguided immune system?

Chemokines and their receptors are key molecules in the development and function of immune cell populations and the organization of lymphoid organs. Despite their central role in immunologic function, genetic studies exploring the intersection of chemokines or their receptors and human health have revealed few associations of unambiguous significance. The best-characterized examples have revealed striking selective advantage conferred by loss of receptors used as portals of entry by pathogens. Recently, mutations in the CXCR4 chemokine receptor gene were identified in a dominantly inherited immunodeficiency disease, WHIM syndrome. Genetic and biochemical evidences suggest that the loss of the receptor cytoplasmic tail domain results in aberrant signaling. Analyses of mutant cell responses to the receptor ligand CXCL12 have revealed enhanced chemotaxis, confirming the gain-of-function effect of the truncation mutations. The clinical features and potential mechanism of immunodeficiency in WHIM syndrome patients are discussed in this review.

Agammaglobulinemia↗
PubMed2001

Presenilin function: connections to Alzheimer's disease and signal transduction.

Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are associated with early-onset familial Alzheimer's disease which displays an accelerated deposition of amyloid plaques and neurofibrillary tangles. Presenilins are multi-spanning transmembrane proteins which localize primarily to the endoplasmic reticulum and the Golgi compartments. We have previously demonstrated that PS1 exists as a high-molecular-mass complex that is likely to contain several functional ligands. Potential binding proteins were screened by the yeast two-hybrid system using the cytoplasmically orientated PS1 loop domain which was shown to interact strongly with members of the armadillo family of proteins, including beta-catenin, p0071 and a novel neuron-specific plakophilin-related armadillo protein (NPRAP). Armadillo proteins can have dual functions that encompass the stabilization of cellular junctions/synapses and the mediation of signal transduction pathways. Our observations suggest that PS1 may contribute to both aspects of armadillo-related pathways involving neurite outgrowth and nuclear translocation of beta-catenin upon activation of the wingless (Wnt) pathway. Alzheimer's disease (AD)-related presenilin mutations exhibit a dominant gain of aberrant function resulting in the prevention of beta-catenin translocation following Wnt signalling. These findings indicate a functional role for PS1 in signalling and suggest that mistrafficking of selected presenilin ligands may be a potential mechanism in the genesis of AD.

Alzheimer Disease↗
PubMedDate not supplied

Familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is inherited in ten percent of cases as a Mendelien trait. Familial ALS (FALS) is genetically heterogeneous and transmitted either as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait. Fifteen percent of DFALS families have mutations in the gene for Cu,Zn superoxide dismutase (SOD1) which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Several observations suggest that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed. The role of eventual neurofilament involvement in the pathogenesis of ALS is also discussed. The locus for one form of RFALS has been mapped to chromosome 2q33. FALS can also be associated with dementia and the gene locus for one form of hereditary ALS-dementia syndrome maps to chromosome 17q21-22.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Nephrogenic syndrome of inappropriate antidiuresis: a novel disorder in water balance in pediatric patients.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We report findings in 2 unrelated male infants whose clinical presentation and laboratory findings were consistent with SIADH, but who exhibited unmeasurable arginine vasopressin (AVP) levels on repeated occasions. We hypothesized that these infants had a novel gain of function defect in the AVP-signaling pathway. DNA sequencing of each patient's vasopressin V2 receptor (V2R) gene identified mutations (R137C or R137L) in each. R137H mutations have been reported previously to cause nephrogenic diabetes insipidus. To further characterize the effects of these mutations, we re-created each mutation by site-directed mutagenesis in a vasopressin V2R expression vector and cotransfected COS-7 cells with wild-type and mutant vasopressin V2R vectors and a cyclic adenosine monophosphate-responsive luciferase reporter plasmid. The luciferase activity was induced 7.5-fold (R137L mutant; P = 0.0037) and 4-fold (R137C mutant; P = 0.013) more than the wild-type vasopressin V2R, which is the empty vector or the inactivating R137H mutant. This novel gain of function mutation in the vasopressin V2R can cause constitutive activation of the receptor and resultant hyponatremia. These findings represent a previously unrecognized genetic disease, which was designated as nephrogenic syndrome of inappropriate antidiuresis. A number of questions have emerged, including the following: (1) What is the frequency? (2) Are there nonrenal manifestations? (3) Are heterozygotes affected? (4) What is the optimal therapy? and (5) How do these mutations cause constitutive activation of the receptor?

Diabetes Insipidus, Nephrogenic↗
PubMed2006

SWI/SNF binding to the HO promoter requires histone acetylation and stimulates TATA-binding protein recruitment.

We use chromatin immunoprecipitation assays to show that the Gcn5 histone acetyltransferase in SAGA is required for SWI/SNF association with the HO promoter and that binding of SWI/SNF and SAGA are interdependent. Previous results showed that SWI/SNF binding to HO was Gcn5 independent, but that work used a strain with a mutation in the Ash1 daughter-specific repressor of HO expression. Here, we show that Ash1 functions as a repressor that inhibits SWI/SNF binding and that Gcn5 is required to overcome Ash1 repression in mother cells to allow HO transcription. Thus, Gcn5 facilitates SWI/SNF binding by antagonizing Ash1. Similarly, a mutation in SIN3, like an ash1 mutation, allows both HO expression and SWI/SNF binding in the absence of Gcn5. Although Ash1 has recently been identified in a Sin3-Rpd3 complex, our genetic analysis shows that Ash1 and Sin3 have distinct functions in regulating HO. Analysis of mutant strains shows that SWI/SNF binding and HO expression are correlated and regulated by histone acetylation. The defect in HO expression caused by a mutant SWI/SNF with a Swi2(E834K) substitution can be partially suppressed by ash1 or spt3 mutation or by a gain-of-function V71E substitution in the TATA-binding protein (TBP). Spt3 inhibits TBP binding at HO, and genetic analysis suggests that Spt3 and TBP(V71E) act in the same pathway, distinct from that of Ash1. We have detected SWI/SNF binding at the HO TATA region, and our results suggest that SWI/SNF, either directly or indirectly, facilitates TBP binding at HO.

Acetylation↗
PubMed1992

Recombinant von Willebrand factor Arg578-->Gln. A type IIB von Willebrand disease mutation affects binding to glycoprotein Ib but not to collagen or heparin.

von Willebrand factor (vWF) is a multimeric plasma glycoprotein that mediates platelet adhesion to the subendothelium via binding to platelet glycoprotein Ib (GPIb) and to components of the vessel wall. Recently, missense mutations that cause type IIB von Willebrand disease (vWD) were described, clustered within a disulfide loop in the A1 domain of vWF that has binding sites for GPIb, collagen, and heparin. In type IIB vWD, plasma vWF exhibits increased affinity for platelet GPIb, but decreased binding to collagen and heparin. The effect was studied of a type IIB vWD mutation, Arg578-->Gln, on the interaction of vWF with GPIb, collagen, and heparin. Recombinant wild type rvWF and mutant rvWF(R578Q) were expressed in COS-7 cells. Ristocetin-induced binding of rvWF(R578Q) to GPIb was markedly increased compared with rvWF, confirming that the Arg578-->Gln mutation causes the characteristic gain-of-function abnormality of type IIB vWD; botrocetin-induced binding was only slightly increased. Binding to collagen type III and heparin-agarose was compared for rvWF(R578Q) and plasma vWF from patients with four different type IIB mutations: Arg543-->Trp, Arg545-->Cys, Val553-->Met, Arg578-->Gln. For all of the plasma samples, binding to collagen and to heparin was reduced compared with normal plasma. In contrast, binding of rvWF(R578Q) to collagen and heparin was normal compared with wild type rvWF. Therefore, the Arg578-->Gln mutation increases the affinity of vWF for GPIb but does not directly impair vWF interaction with collagen or heparin. Arg578 may therefore be necessary to prevent normal vWF from interacting with GPIb. In type IIB vWD, the defective binding of plasma vWF to collagen and heparin may be secondary to post-synthetic modifications that occur in vivo, such as the loss of high molecular weight vWF multimers.

Amino Acid Sequence↗
PubMed2005

Li-Fraumeni syndrome: a p53 family affair.

The p53 alterations frequently found in human tumors are missense mutations in the DNA binding domain. These p53 mutations have been shown to have gain-of-function or dominant-negative properties in multiple experiments. The consequences of these p53 mutations at physiological levels on the development of a tumor were unclear. Using mouse models, three recent papers have shed light on the mechanisms of mutant p53 and its family members, p63 and p73, in tumorigenesis. Interestingly, the p53 point mutant mice had a similar phenotype to p53 family compound mutant mice suggesting that there is an interplay between the p53 family members in tumorigenesis and Li-Fraumeni syndrome.

Animals↗
PubMed2006

Functional significance of the kainate receptor GluR6(M836I) mutation that is linked to autism.

Previous studies revealed a linkage of the kainate receptor GluR6 with autism, a pervasive developmental disorder. Mutational screening in autistic patients disclosed the amino acid exchange M836I in a highly conserved domain of the cytoplasmic C-terminal region of GluR6. Here, we show that this mutation leads to GluR6 gain-of-function. By using the two-electrode voltage clamp technique we observed a significant increase of current amplitudes of mutant GluR6 compared to wild type GluR6. Western blotting of oocytes injected with mutant or wild type GluR6 cRNA and transfection of EGFP-tagged GluR6 receptors into COS-7 cells revealed an enhanced plasma membrane expression of GluR6(M836I) compared to wild type GluR6. Membrane expression of GluR6(M836I) but not of wild type GluR6 seems to be regulated by Rab11 as indicated by our finding that GluR6(M836I) but not wild type GluR6 showed increased current amplitudes and protein expression when coexpressed with Rab11. Furthermore, injection of GTP plus Rab11A protein into oocytes increased current amplitudes in GluR6(M836I) but not in wild type GluR6. By contrast, Rab5 downregulated the currents in oocytes expressing wild type GluR6 but had only little, statistically not significant effects on currents in oocytes expressing GluR6(M836I). Our data on altered functional properties of GluR6(M836I) provide a functional basis for the postulated linkage of GluR6 to autism. Furthermore, we identified new mechanisms determining the plasma membrane abundance of wild type GluR6 and GluR6(M836I).

Amino Acid Substitution↗
PubMed2004

Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death.

OBJECTIVES: Point mutations in the cardiac ryanodine receptor (RyR2) mediate abnormal intracellular Ca(2+) release and are associated with stress-induced ventricular tachycardia (VT), leading to sudden cardiac death (SCD). Although the precise molecular basis of RyR2 dysfunction in SCD remains controversial, there is consensus that the mutations characterised to date all exhibit gain-of-function Ca(2+) release properties following cell stimulation. We investigated the functional impact of a distinct set of SCD-linked RyR2 mutations (L(433)P, N(2386)I, R(176)Q/T(2504)M) on intracellular Ca(2+) handling. METHODS: We expressed full-length recombinant human wild-type (WT) and SCD-linked RyR2 mutations in human embryonic kidney (HEK) cells, and profiled the spatial and amplitude characteristics of caffeine-evoked Ca(2+) release through homo-tetrameric channels in living cells using rapid confocal laser scanning microscopy. RESULTS: Analysis of the precise mode of Ca(2+) release in HEK cells expressing RyR2 mutants demonstrated profound differences when compared with WT channels. The SCD-linked RyR2 mutations characterised in this study exhibited heterogeneous Ca(2+) release profiles, including the novel observation that one of the mutants, (L(433)P), exhibited a marked reduction in sensitivity to channel activation. However, all SCD-linked RyR2 mutations characterised in this study resulted in an increased duration of elevated cytoplasmic Ca(2+) levels following channel activation. CONCLUSIONS: Our live cell-based data demonstrates functional heterogeneity of Ca(2+) release through SCD-linked RyR2 mutants, suggesting that the mechanistic basis of RyR2 dysfunction in SCD may be more complex than previously anticipated. These findings may have profound consequences for the therapeutic modulation of RyR2 in stress-induced VT and SCD.

Arrhythmias, Cardiac↗
PubMed1998

Molecular approaches to renal physiology and therapeutics.

The recent development of methods to transfer, mutate, or ablate genes in vivo has provided renal investigators and physicians with powerful tools to explore normal renal physiology, the pathophysiological basis of renal disease, and potential therapeutic interventions. The use of transgenic and knockout mice to produce gain-of-function and loss-of-function mutations, and to create animal models of human hereditary renal diseases, permits unprecedented versatility and power of experimental design. Conditional and inducible gene targeting methods to control the temporal and spatial expression of transgenes offer considerable promise in studying the impact of normal and disease genes in the kidney. In vivo gene transfer of encoding DNAs, antisense DNA and RNA, and cis-element decoys allows manipulation of specific genes in somatic cells. Liposome-mediated, virally mediated, and ex vivo transduced renal cells represent novel approaches to facilitate in vivo gene transfer to the kidney.

Animals↗
PubMed2005

[The genetic disorders responsible for sudden cardiac death].

Sudden cardiac death is defined as an unpredictable death within 24 hours. It is estimated to occur with a frequency of more than 50,000 per year in Japan. The inherited arrhythmogenic diseases associated with the transmembranous ionic channels, anchoring proteins or intracellular calcium regulating proteins are thought to be responsible for sudden cardiac death in infants, children, and young adults who have structurally normal hearts. Recent genetic analyses have identified congenital diseases such as the long-QT syndrome (LQTS), the Jervell and Lange-Nielsen syndrome (JLNS), the Brugada syndrome (BrS), the short-QT syndrome (SQTS), the arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2), and the catecholamine-induced polymorphic ventricular tachycardia (CPVT) /familial polymorphic ventricular tachycardia (FPVT). Loss of function in the slow component of the delayed rectifier potassium current (I(Ks)) channels (KCNQ1, KCNE1), the rapid component of the potassium current (I(Kr)) channels (KCNH2, KCNE2) and the inward rectifier potassium current (I(Kl), Kir2.1) channel (KCNJ2) is linked to the LQTSs (type 1, 2, 5, 6, and 7 (Andersen syndrome)) and the JLNSs (type 1 and 2). Changes of function in the alpha-subunit of cardiac sodium channels (SCN5A) is also linked to the LQTS type 3 and the BrS. A mutation in the ankyrin-B, anchoring proteins, has been identified as cause of the LQTS type 4. The SQTS is caused by gain of function in the KCNH2. Further, the missense mutations in the gene encoding ryanodine receptor 2 (RyR2) or calsequestrin 2 (CASQ2) that regulate intra-cardiac calcium handling is possibly implicated in the ARVC2 and the CPVT/FPVT. Herein, we present a review of the literature regarding the genetic mechanisms of the inherited arrhythmogenic diseases.

Adult↗
PubMed1995

Response of heat shock element within the human HSP70 promoter to mutated p53 genes.

Recent studies have demonstrated that mutation of the p53 gene caused a gain of new functions such as transforming activation, binding to heat shock cognate protein 70 and/or transactivation of a variety of promoters. In the course of seeking the biochemical basis for the gain of these functions, we have noticed the correlation between transforming activity of different mutated p53 genes and their transactivational activity on the human heat shock protein 70 promoter. Analysis of 5' deletion constructs of the heat shock protein 70 promoter showed that some specific elements within the heat shock domain containing two heat shock elements (HSEs) could respond to mutant p53 species but not basic promoter elements such as the TATA box, CCAAT box, and GC box. Subsequently, we identified the HSE as a responsive element using reporter constructs of minimal promoter containing synthetic proximal HSE, distal HSE, or GC/CCAAT box. Further analysis using in vitro mutagenesis of HSE suggests that HSE with heat shock factor binding ability is required for transactivation of the heat shock protein 70 promoter by mutated p53 genes.

Base Sequence↗
PubMed2003

Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia.

BACKGROUND: Many long-QT syndrome (LQTS) mutations in the cardiac Na+ channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (Isus) during depolarization. However, some Na+ channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase Isus (<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype. METHODS AND RESULTS: We developed new experimental approaches based on theoretical analyses to investigate Na+ channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation. CONCLUSIONS: Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.

Action Potentials↗
PubMed2006

Preferential silencing of a common dominant rhodopsin mutation does not inhibit retinal degeneration in a transgenic model.

Autosomal dominant retinitis pigmentosa caused by the frequent rhodopsin P23H mutation is characterized by progressive photoreceptor cell death eventually leading to blindness and for which no therapies are available. Considering the gain-of-function effect exerted by the P23H mutation, strategies aimed at silencing the expression of the mutated allele, like RNA interference, are desirable. We have designed small interfering RNAs (siRNA) to silence specifically the P23H rhodopsin allele expressed by a transgenic rat model of the disease. We have selected in vitro one siRNA and generated an adeno-associated viral (AAV) vector expressing the short hairpin RNA (shRNA) based on the selected siRNA. In vitro the shRNA significantly inhibits the expression of the P23H but not the wild-type rhodopsin allele. Subretinal administration of the AAV2/5 vector encoding the shRNA in P23H transgenic rats results in inhibition of rhodopsin P23H expression that is not able to prevent or block photoreceptor degeneration. Since rhodopsin is the most abundant rod photoreceptor protein, systems resulting in more robust shRNA expression in the retina may be required to achieve therapeutic efficacy in vivo.

Alleles↗
PubMed2005

Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function?

Spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. Most of the SMN1 transcript is full-length, whereas a substantial proportion of the SMN2 transcript lacks exon 7 (delta7). We characterized the developmental expression of SMN2 by comparing control and SMA fetuses. The control spinal cord revealed the highest amount of FL SMN, most of which was of SMN1 origin. When analyzing the SMA spinal cord transcripts, we detected a considerable reduction in the FL/delta7 ratios due to a decrease in the FL and an increase in delta7 isoform. After immunoblot and immunohistochemistry analyses, we found that the amount of SMN2 protein in the SMA spinal cord and muscle was lower than in the controls. However, the results of the expression of SMN2 in intestine, lung, adrenal gland, kidney, and eye, which are unaffected by the disease, were the same in controls and SMA samples. In these tissues, SMN2 may compensate for the absence of SMN1, whereas in SMA motor neurons, a cell-specific dysregulation of the SMN2 expression could favor the onset of the acute form of the disease.

Age Factors↗
PubMed1997

HLA-H and associated proteins in patients with hemochromatosis.

BACKGROUND: The 845A(C282Y) mutation in the HLA-H gene accounts for most cases of hereditary hemochromatosis in patients who are of European origin. Some lack this mutation, however, and it is not present in Asian patients. Thus, other mutations either in HLA-H or associated proteins may be present in such patients. HLA-H associates with beta-2-microglobulin. Calreticulin associates with class 1 HLA proteins and appears to be identical with mobilferrin, a putative iron transport protein. These two proteins are therefore candidates for mutations in patients with hemochromatosis. MATERIALS AND METHODS: We have sequenced the coding region and parts of introns of the HLA-H gene, the beta-2-microglobulin gene, and the calreticulin (mobilferrin) gene of 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the 845A(C282Y) mutation. The number of chromosomes at risk studied were 18 for HLA-H, 14 for beta-2-microglobulin and 10 for calreticulin. RESULTS: We detected 3 new intronic polymorphisms in the HLA-H gene, each a point mutation. Some differences from published sequences of beta-2-microglobulin and calreticulin were documented, but these were uniformly present in all samples. CONCLUSIONS: The lack of additional mutations in the HLA-H gene is remarkable, and we speculate that the C282Y mutation may be a gain-of-function change.

Asia↗
PubMed1991

Two C. elegans genes control the programmed deaths of specific cells in the pharynx.

The genes ces-1 and ces-2 control the decisions of two cells in the nematode Caenorhabditis elegans to undergo programmed cell death. Mutations that cause a gain of ces-1 function or a reduction of ces-2 function prevent these cells, the sisters of the two pharyngeal NSM neurons, from dying. These mutations do not affect most other cell deaths. Genetic studies indicate that ces-1 and ces-2 affect the fates of the NSM sisters by regulating the genes required for all programmed cell deaths to occur.

Animals↗