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Results for “Loss of function”

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PubMed2004

Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.

Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells.

Base Sequence↗

PubMed2004

Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.

Alveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing.

ADP-Ribosylation Factors↗

PubMed2004

Loss-of-function polymorphic variants of the human angiotensin II type 1 receptor.

The angiotensin II type 1 (AT1) receptor is the primary effector for angiotensin II (Ang II), a key peptide regulator of blood pressure and fluid homeostasis. AT1 receptors are involved in the pathogenesis of several cardiovascular diseases, including hypertension, cardiac hypertrophy, and congestive heart failure, which are characterized by significant interindividual variation in disease risk, progression, and response to pharmacotherapy. Such variation could arise from genomic polymorphisms in the AT1 receptor. To pursue this notion, we have pharmacologically characterized seven known and putative nonsynonymous AT1 receptor variants. Functional analysis using the cell-based assay receptor selection and amplification technology (R-SAT) revealed that three variants (AT1-G45R, AT1-F204S, and AT1-C289W) displayed altered responses to Ang II and other AT1 receptor agonists and antagonists. Agonist responses to Ang II were absent for AT1-G45R and significantly reduced in potency for AT1-C289W (11-fold) and AT1-F204S (57-fold) compared with the wild-type (WT) receptor. AT1-F204S also displayed reduced relative efficacy (57%). Quantitatively similar results were obtained in two additional functional assays, phosphatidyl inositol hydrolysis and extracellular signal-regulated kinase activation. Radioligand binding studies revealed that AT1-G45R failed to bind Ang II, whereas cell surface staining clearly showed that it trafficked to the cell surface. AT1-C289W and AT1-F204S displayed reduced binding affinities of 3- and 5-fold and reduced cell surface expression of 43 and 60% of that observed for the WT receptor, respectively. These data demonstrate that polymorphic variation in the human AT1 receptor induces loss of functional phenotypes, which may constitute the molecular basis of variability of AT1 receptor-mediated physiological responses.

Amino Acid Sequence↗

PubMed2000

p21(WAF-1/CIP-1), a downstream regulator of functional p53 loss, in transitional cell carcinoma of urothelium.

OBJECTIVES: The expression of p21(WAF-1/CIP-1), a downstream regulator of p53, is a universal cycline-dependent kinase inhibitor. The aim of this study is to determine whether p21 expression could be used as a prognostic marker in urothelial carcinomas. METHODS: By use of immunohistochemistry, we examined the expression of p21(WAF-1/CIP-1) in 60 patients with urothelial carcinomas and compared the results with the status of nuclear p53 and mdm2 accumulation, expression of type IV collagen in the basement membranes and upregulation of metalloproteinases (MMP-1, MMP-2, MMP-9). RESULTS: p21(WAF-1/CIP-1) immunoreactivity was observed in 51.7% of the tumors, and in only 39% of the tumors with functional p53 loss (nuclear accumulation of p53 and/or mdm2). p21(WAF-1/CIP-1) overexpression was not associated with grade and stage of the tumors and presence or absence of concomitant CIS. Moreover, p21(WAF-1/CIP-1) overexpression was not associated with upregulation of metalloproteinases or destruction of type IV collagen of basement membranes. CONCLUSIONS: Our results suggest that p21(WAF-1/CIP-1) expression is regulated by both p53-dependent and independent pathways and is not related to grade, stage or potential markers of invasion in urothelial carcinomas.

Adult↗

PubMed2003

C-reactive protein is associated with renal function abnormalities in a non-diabetic population.

BACKGROUND: C-reactive protein (CRP) has recently been introduced in cardiovascular medicine as a predictor of myocardial infarction, stroke and peripheral artery disease in different populations. We hypothesized that elevated CRP levels are associated with renal function abnormalities. METHODS: To test this hypothesis, we studied the relationship between CRP levels and renal function loss measured as diminished creatinine clearance in a large non-diabetic population (7317 subjects). In addition, the associations and confounding effects of established renal risk factors that could explain the association between CRP and diminished renal filtration were studied. Also, the association of CRP with early alterations in renal function, such as those evidenced by a relatively high glomerular filtration ("hyperfiltration"), was examined. CRP levels were divided in quartiles. Subjects with CRP levels within the first quartile were defined as the reference group. Diminished renal filtration and hyperfiltration were defined as a creatinine clearance below or exceeding two times the prediction interval of the age- and sex-related reference group. RESULTS: Elevated CRP levels were positively associated with cardiovascular and renal risk factors: age, body mass index, blood pressure, serum cholesterol level, smoking, plasma glucose level and elevated urinary albumin excretion. Elevated CRP was positively associated with diminished filtration (OR 1.8; 95% CI 1.2 to 2.6). In multivariate analyses, CRP was independently associated with a diminished filtration (OR 1.9; 95% CI 1.3 to 2.9). Interestingly, CRP also was associated with hyperfiltration (highest quartile, OR 1.7; 95% CI 1.2 to 2.5). However, body mass index accounted for most of the relationship between CRP and hyperfiltration. CONCLUSIONS: As in cardiovascular disease, CRP appears to be a risk marker for renal function loss. The mechanism of this relationship remains to be clarified. However, the association between CRP, body weight, and a relatively elevated creatinine clearance is a hypothesis-generating finding, suggesting that early inflammatory processes related to high body fat may predispose the kidney to glomerular hyperfiltration-related renal function loss.

Adult↗

PubMed1999

Disability in ankylosing spondylitis.

PURPOSE: This study was designed to examine the functional loss in ankylosing spondylitis and explore the relationship between disability and various factors such as age, disease duration, disease activity, spinal mobility, chest expansion, peripheral joint involvement, radiological changes, and psychosocial well-being. METHOD: Forty-two patients were included in this cross-sectional study. RESULTS: The results showed that 37 patients had mild to moderate disability, two patients had severe disability, and three patients did not report any functional loss. Spearman correlation analyses showed that disability was strongly correlated with spinal mobility measures, disease activity measures, and disease duration. Also, patients with peripheral joint involvement had greater disability. When the predictive effect of five independent variables was studied by multiple regression analysis, it was found that the most powerful predictors of functional loss in AS patients were cervical rotation, modified Schober's test, and pain. CONCLUSIONS: These data suggest that functional consequences of AS are constituted by multiple impairments and each needs to be managed by an integrated physiatric approach.

Activities of Daily Living↗

PubMed2000

Characterization of human CYP2G genes: widespread loss-of-function mutations and genetic polymorphism.

CYP2G1 is an abundant, olfactory mucosa-specific cytochrome P450 enzyme active in the metabolism of sex steroids and xenobiotic substrates in mammalian animals. Two different human CYP2G genes, CYP2GP1 and CYP2GP2, were characterized in the present study. Polymorphisms in these genes were also studied. CYP2GP1 contained a single nucleotide deletion in exon 2 (deltaC) and a 2.4-kb deletion between exons 3 and 7 (deltaE4-6), whereas CYP2GP2 contained a nonsense mutation in exon 1 and another in exon 3. The coding region sequences in exons 1-3 and 7-9 of the two genes were 96.7% identical. Both genes were localized to human chromosome 19, and Southern blot analysis of human genomic DNA did not detect any additional copies of the CYP2G gene. The occurrence of these loss-of-function mutations was analysed by polymerase chain reaction-based genotyping in more than 200 individuals. The deltaE4-6 deletion in CYP2GP1 was detected in 94% of subjects (either homozygous or heterozygous), and an allele which does not contain this deletion was detected in 11.6% of individuals. The nonsense mutation in CYP2GP2 exon 3 was detected in 86% of individuals (either homozygous or heterozygous); however, a potentially functional CYP2GP2 allele based on the absence of the nonsense mutation in exon 3 was also detected in 31% of individuals. These results indicate that a functional CYP2G allele is rare in humans. Analysis of the allelic distribution in different ethnic groups suggested that a functional CYP2G allele, if present, is more likely to be found in Black and Hispanic subjects.

Alleles↗

PubMed2004

Novel loss-of-function mutations of the haematopoiesis-related transcription factor, acute myeloid leukaemia 1/runt-related transcription factor 1, detected in acute myeloblastic leukaemia and myelodysplastic syndrome.

AML1/RUNX1, which encodes a transcription factor essential for definitive haematopoiesis, is a frequent target of leukaemia-associated chromosome translocations. Point mutations of this gene have also recently been associated with leukaemia and myelodysplastic syndrome (MDS). To further define the frequency and biological characteristics of AML1 mutations, we have examined 170 cases of such diseases. Mutations within the runt-domain were identified in five cases: one of de novo acute myeloid leukaemia (AML) and four of MDS. Where multiple time point samples were available, mutations were detected in the earliest samples, which persisted throughout the disease course. Of the five mutations, one was a silent mutation, two were apparent loss-of-function mutations caused by N-terminal truncation, and two were insertions, I150ins and K168ins, which preserved most of the AML1 DNA-binding domain. Both AML1 molecules with insertion mutations were non-functional in that they were unable to rescue haematological defects in AML1-deficient mouse embryonic stem cells. In addition, activating mutations of N-ras, deletion of chromosome 12p, or inactivation of TP53 accompanied some of the AML1 mutations. Together, these observations strongly suggest that one-allele inactivation of AML1 serves as an initial or early event that plays an important role in the eventual development of overt diseases with additional genetic alterations.

Aged↗

PubMed1999

Loss of function mutations of the GnRH receptor: a new cause of hypogonadotropic hypogonadism.

The association of hypogonadotropic hypogonadism with anosmia defines Kallmann's syndrome. The gene of the X-linked form of this syndrome has been cloned and several mutations described. However, the relatively small number of hypogonadotropic hypogonadic patients with Kallmann's gene defects supports the hypothesis that other genes may be involved. Idiopathic hypogonadotropic hypogonadism (IHH) is not associated with anosmia. The GnRH gene was excluded as a candidate gene in IHH since no abnormality was found in several patients. The action of the GnRH is mediated through a G-protein coupled receptor present in the cell membrane of gonadotropes. The GnRH receptor was thus another candidate gene. Recently, we described the first patient with partial hypogonadotropic hypogonadism without anosmia caused by loss of function mutations of the GnRH receptor. We compare this first family with a new family presenting complete hypogonadotropic hypogonadism and a variable degree of gonadotrope deficiency in the affected kindred, and discuss genotype-phenotype correlation.

Family Health↗

PubMed2001

F X Nottingham and F X Taunton. Two novel mutations in factor X resulting in loss of functional activity and an interpretation using molecular modelling.

We report two novel mutations in the Factor X gene which result in a bleeding tendency in two unrelated Caucasian families. Although the mutations occur at adjacent codons in exon 8 and result in reduced functional activity with normal antigen levels, the patterns of inheritance appear to be quite distinct. Factor X Nottingham (alanine 404 threonine) appears to be associated with an autosomal recessive pattern of inheritance. In contrast, Factor X Taunton (arginine 405 glycine) results in a mode of inheritance consistent with an autosomal dominant pattern, all five of the heterozygotes in this family being clinically affected. Molecular modelling studies suggest that, in the case of Factor X Nottingham, a drastic conformational change causes major unfolding of the protein. For Factor X Taunton, less extreme conformational changes occur causing loss of functional activity such that substrate binding sites might be maintained. It is proposed that competition with wild type for substrate binding could occur leading to a dominant negative effect.

Adolescent↗

PubMed2003

Loss-of-function of an N-acetylglucosaminyltransferase, POMGnT1, in muscle-eye-brain disease.

Muscle-eye-brain disease (MEB), an autosomal recessive disorder, is characterized by congenital muscular dystrophy, brain malformation, and ocular abnormalities. Previously, we found that MEB is caused by mutations in the gene encoding the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1), which is responsible for the formation of the GlcNAcbeta1-2Man linkage of O-mannosyl glycan. Although 13 mutations have been identified in patients with MEB, only the protein with the most frequently observed splicing site mutation has been studied. This protein was found to have no activity. Here, we expressed the remaining mutant POMGnT1s and found that none of them had any activity. These results clearly demonstrate that MEB is inherited as a loss-of-function of POMGnT1.

Abnormalities, Multiple↗

PubMed2000

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Adaptor Proteins, Signal Transducing↗

PubMed1997

EGF receptor binding and transformation by v-cbl is ablated by the introduction of a loss-of-function mutation from the Caenorhabditis elegans sli-1 gene.

The 120 kD product of the c-cbl oncogene is rapidly tyrosine phosphorylated and recruited to the EGF receptor following ligand binding. Cbl's oncogenic potential is activated by a large carboxy-terminal truncation that generated v-cbl and removes the Ring finger and proline-rich SH3-binding domains. Here we show that this truncation reveals a novel and highly conserved domain that can interact directly with the EGF receptor in a phosphorylation dependent manner. Furthermore we demonstrate that the v-cbl domain is not utilized by c-cbl for recruitment to the receptor since this binding property is not evident in c-cbl constructs with proline domain deletions, and it is only revealed following deletion of the Ring finger. We also analyse a loss-of-function mutation from the C. elegans homologue, sli-1, and show that the corresponding mutation in v-cbl ablates transformation and EGF receptor association. Thus our findings provide further evidence that v-cbl possesses a novel and evolutionarily conserved phosphotyrosine binding domain and that the dual capability of EGF receptor binding by cbl involves two distinct mechanisms. In addition these findings raise the possibility that v-cbl may transform by competing with c-cbl for phosphorylated binding sites on activated receptor complexes.

3T3 Cells↗

PubMed1991

Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass.

The use of aprotinin to reduce blood loss after cardiopulmonary bypass is under debate. Concern has been raised about the renal effects of aprotinin. We administered a mean aprotinin dose of 4.2 x 10(6) kallikrein-inhibiting units to 13 patients with coronary disease undergoing cardiopulmonary bypass for 74 +/- 5 minutes (mean +/- standard error of the mean); 13 comparable patients having cardiopulmonary bypass served as control subjects, and all were studied postoperatively for 24 hours. Aprotinin reduced postoperative blood loss by 50% (p = 0.0082). Two of the 13 patients who received aprotinin needed one red cell unit each versus a total of 18 units in eight of 13 control patients (p = 0.0096). Blood pressure, hemoglobin value and serum protein concentration were higher after operation in the aprotinin group (p less than 0.05 to p less than 0.01). Platelet counts did not differ, but plasma thromboxane was lower in aprotinin recipients (p less than 0.001). In control patients fibrinogen degradation products (D dimer) doubled, and alpha 2-antiplasmin activity was halved during and after cardiopulmonary bypass (p less than 0.01 to p less than 0.001), whereas aprotinin patients showed no changes. The complement breakdown products C4a, C3a, and C3dg as well as C9 neoantigen increased from prebypass baseline in both groups (p less than 0.001); the increment of C3a and C3dg was greater in the aprotinin than in the control patients (p less than 0.001). Serum electrolytes, osmolality, and creatinine remained normal in both groups of patients. Creatinine clearance was normal or above normal and virtually identical in both groups. Osmolar clearance and fractional sodium excretion were higher in the aprotinin group than in the control group shortly after cardiopulmonary bypass (p less than 0.05 to p less than 0.01); renal function was unremarkable the next morning. No adverse clinical effects attributable to aprotinin were seen. In summary, aprotinin offers advantages for cardiopulmonary bypass.

Antithrombin III↗

PubMed2006

Endowing self-binding feature restores the activities of a loss-of-function chimerized anti-GM2 antibody.

Our previous studies have described a rare type of antibody that spontaneously binds to itself, or homodimerizes. This self-binding, or autophilic antibody provides stronger protection against bacterial infection than a non-self-binding antibody with identical specificity and affinity, due to an increase of polymeric avidity. Furthermore, we have shown that a peptide derived from the self-binding domain of the autophilic T15 antibody can be crosslinked to the Fc carbohydrate of monoclonal antibodies specific for the B-cell receptor of B-cell tumors. These peptide-crosslinked antibodies can exert self-binding properties, leading to an increase in binding efficiency to the target cells as well as an increase in potential to induce apoptosis. Herein, we report a novel finding that crosslinking of the autophilic T15 peptide rescues a loss-of-function chimerized (ch) anti-GM2 antibody. The parental antibody demonstrates in vivo anti-tumor activity against melanoma xenografts. The T15 peptide-conjugated antibody shows the ability to bind to itself, as well as an increased binding to its antigen, ganglioside GM2. Moreover, the peptide-conjugated antibody also demonstrates an increased ability to bind to two GM2-positive tumor cell lines and notably important, restores its ability to induce apoptosis in two types of tumor cells. These results provide strong support for the clinical potential of the autophilic technology.

Antibodies, Monoclonal↗

PubMed2003

Analysis of combinatorial loss-of-function mutants in the Arabidopsis ethylene receptors reveals that the ers1 etr1 double mutant has severe developmental defects that are EIN2 dependent.

Ethylene responses in Arabidopsis are controlled by the ETR receptor family. The receptors function as negative regulators of downstream signal transduction components and fall into two distinct subfamilies based on sequence similarity. To clarify the levels of functional redundancy between receptor isoforms, combinatorial mutant lines were generated that included the newly isolated ers1-2 allele. Based on the etiolated seedling growth response, all mutant combinations tested exhibited some constitutive ethylene responsiveness but also remained responsive to exogenous ethylene, indicating that all five receptor isoforms can contribute to signaling and no one receptor subtype is essential. On the other hand, light-grown seedlings and adult ers1 etr1 double mutants exhibited severe phenotypes such as miniature rosette size, delayed flowering, and sterility, revealing a distinct role for subfamily I receptors in light-grown plants. Introduction of an ein2 loss-of-function mutation into the ers1 etr1 double mutant line resulted in plants that phenocopy ein2 single mutants, indicating that all phenotypes observed in the ers1 etr1 double mutant are EIN2 dependent.

Arabidopsis↗

PubMed2006

Functional significance of using tissue adhesive substance in nephron-sparing surgery: assessment by quantitative SPECT of 99m Tc-Dimercaptosuccinic acid scintigraphy.

OBJECTIVES: To compare changes in renal function following nephron-sparing surgery (NSS) using tissue adhesive only versus NSS using standard suturing technique, as measured by quantitative SPECT of 99m Tc-dimercaptosuccinic acid uptake by the kidney (QDMSA). MATERIALS AND METHODS: QDMSA was done before and 3-6 mo after the operation in 32 patients who underwent standard suturing technique and in 24 patients in whom tissue adhesive sealant (19 with albumin glutaraldehyde tissue adhesive [BioGlue]; 5 with CoSeal) was used to close the parenchymal defect. Individual kidney uptake was measured and retrospectively compared between the two groups. RESULTS: Average tumor diameter was 3.4cm (range: 2.2-6) in the suture group and 3.56 (range: 1.7-6) in the tissue sealant group. In the tissue sealant group following surgery, we observed an average individual renal function loss of 11.49% compared with the suture group in whom an average individual renal function loss of 20.36% (p = 0.02) was measured by 99m Tc-DMSA. CONCLUSIONS: The use of tissue sealant to close the parenchymal defect during NSS demonstrated a statistically significant advantage in reducing functioning renal loss as measured by the absolute uptake of QDMSA. Further clinical studies are required to establish the role of tissue sealants in NSS.

Adult↗

PubMed2004

Loss of function but no gain of function caused by amino acid substitutions in the hexapeptide of Hoxa1 in vivo.

Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

Amino Acid Substitution↗