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PubMed1995

The role of gsc and BMP-4 in dorsal-ventral patterning of the marginal zone in Xenopus: a loss-of-function study using antisense RNA.

The dorsal-specific homeobox gene goosecoid (gsc) and the bone morphogenetic protein 4 gene (BMP-4) are expressed in complementary regions of the Xenopus gastrula. Injection of gsc mRNA dorsalizes ventral mesodermal tissue and can induce axis formation in normal and UV-ventralized embryos. On the other hand, BMP-4 mRNA injection, which has a strong ventralizing effect on whole embryos, has been implicated in ventralization by UV, and can rescue tail structures in embryos dorsalized by LiCl. The above-mentioned putative roles for BMP-4 and gsc are based on gain-of-function experiments. In order to determine the in vivo role of these two genes in the patterning of the Xenopus mesoderm during gastrulation, partial loss-of-function experiments were performed using antisense RNA injections. Using marker genes that are expressed early in gastrulation, we show that antisense gsc RNA has a ventralizing effect on embryos, whereas antisense BMP-4 RNA dorsalizes mesodermal tissue. These loss-of-function studies also show a requirement for gsc and BMP-4 in the dorsalization induced by LiCl and in the ventralization generated by UV irradiation, respectively. Thus, both gain- and loss-of-function results for gsc and BMP-4 support the view that these two genes are necessary components of the dorsal and ventral patterning pathways in Xenopus embryos.

Animals↗

PubMed1994

[Early and late damage to the auditory and vestibular area after meningitis in childhood and adolescence].

Meningitis is still one of the serious infectious diseases in clinical practise. In a high percentage of cases with this disease process, the auditory and vestibular parts of the inner ear are damaged. In this study the auditory and vestibular systems of 53 children and teenagers between 1.7 and 18.7 years of age were examined following meningitis. The mean time-interval between meningitis and examination was 5.8 years. Eighty-one of 106 ears examined showed sensorineural hearing losses which varied between mild hearing loss and total deafness. Peripheral vestibular lesions were found in 60 of 106 labyrinths examined. These varied between inhibition and total loss of function. In addition, we also found central vestibular lesions in 29 cases. Mild and moderate combined auditory and vestibular lesions could be verified in 23 ears, whereas profound functional disturbances or functional losses were found in 29 ears examined. Eight of 40 ears with hearing losses and 12 of 40 ears with peripheral vestibular lesions showed progression during follow-up. The findings of this study emphasize the need for auditory and vestibular diagnostic studies followed meningitis in children and teenagers. Patients and their families should be cared for on a long-term basis to avoid social and psychological problems.

Adolescent↗

PubMed1998

Smad4 (DPC4)--a potent tumour suppressor?

The recently described family of Smad molecules are essential mediators of transforming growth factor beta (TGF-beta) signalling. To date, seven members of this family have been identified, each of which plays a specific and separate role in mediating TGF-beta superfamily gene transcription. At least two different Smads, Smad2 and Smad4 (DPC4), have been implicated in human cancer and appear to have tumour-suppressor functions. Loss of function of Smad4 is most strongly associated with human pancreatic and colorectal malignancy. Furthermore, work from several different groups has suggested associations between Smad4 loss and malignancy in a number of other tissues. Here, we present a review of the current state of the literature implicating the central Smad mediator, Smad4, in the development of cancer.

Animals↗

PubMed2024

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Humans↗

PubMed2005

Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression.

Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.

Adult↗

PubMedDate not supplied

POEM: Parameter Optimization using Ensemble Methods: application to target specific scoring functions.

In computational biology processes such as docking, binding, and folding are often described by simplified, empirical models. These models are fitted to physical properties of the process by adjustable parameters. An appropriate choice of these parameters is crucial for the quality of the models. Locating the best choices for the parameters is often is a difficult task, depending on the complexity of the model. We describe a new method and program, POEM (Parameter Optimization using Ensemble Methods), for this task. In POEM we combine the DOE (Design Of Experiment) procedure with ensembles of different regression methods. We apply the method to the optimization of target specific scoring functions in molecular docking. The method consists of an iterative procedure that uses alternate evaluation and prediction steps. During each cycle of optimization we fit an approximate function to a defined loss function landscape and improve the quality of this fit from cycle to cycle by constantly augmenting our data set. As test applications we fitted the FlexX and Screenscore scoring functions to the kinase and ATPase protein classes. The results are promising: Starting from random parameters we are able to locate parameter sets which show superior performance compared to the original values. The POEM approach converges quickly and the approximated loss function landscapes are smooth, thus making the approach a suitable method for optimizations on rugged landscapes.

Adenosine Triphosphatases↗

PubMed2004

RNAi living-cell microarrays for loss-of-function screens in Drosophila melanogaster cells.

RNA interference (RNAi)-mediated loss-of-function screening in Drosophila melanogaster tissue culture cells is a powerful method for identifying the genes underlying cell biological functions and for annotating the fly genome. Here we describe the development of living-cell microarrays for screening large collections of RNAi-inducing double-stranded RNAs (dsRNAs) in Drosophila cells. The features of the microarrays consist of clusters of cells 200 mum in diameter, each with an RNAi-mediated depletion of a specific gene product. Because of the small size of the features, thousands of distinct dsRNAs can be screened on a single chip. The microarrays are suitable for quantitative and high-content cellular phenotyping and, in combination screens, for the identification of genetic suppressors, enhancers and synthetic lethal interactions. We used a prototype cell microarray with 384 different dsRNAs to identify previously unknown genes that affect cell proliferation and morphology, and, in a combination screen, that regulate dAkt/dPKB phosphorylation in the absence of dPTEN expression.

Animals↗

PubMed1996

Four families with loss of function mutations of the thyrotropin receptor.

We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro162 Ala substitution. The three other were compound heterozygotes: 1) Gln324-->Stop and Asp410 Asn2), Cys41 Ser and Phe525 Leu, 3) Cys390 Trp and Trp546-->Stop. In all patients, the plasma TSH concentration was increased, whereas T3 and T4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects. Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys390 Trp abolished high affinity hormone binding. Receptor mutated at Asp410 Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe525 Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.

Adenylyl Cyclases↗

PubMed2002

Friedreich ataxia: a paradigm for mitochondrial diseases.

Friedreich ataxia (FRDA), a progressive neurodegenerative disease, is due to the partial loss of function of frataxin, a mitochondrial protein of unknown function. Loss of frataxin causes mitochondrial iron accumulation, deficiency in the activities of iron-sulfur (Fe-S) proteins, and increased oxidative stress. Mouse models for FRDA demonstrate that the Fe-S deficit precedes iron accumulation, suggesting that iron accumulation is a secondary event. Furthermore, increased oxidative stress in FRDA patients has been demonstrated, and in vitro experiments imply that the frataxin defect impairs early antioxidant defenses. These results taken together suggest that frataxin may function either in mitochondrial iron homeostasis, in Fe-S cluster biogenesis, or directly in the response to oxidative stress. It is clear, however, that the pathogenic mechanism in FRDA involves free-radical production and oxidative stress, a process that appears to be sensitive to antioxidant therapies.

Animals↗

PubMed2005

Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor.

The genetic hallmark of hemangioblastomas and clear cell-renal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxia-inducible factor-1alpha (HIF-1alpha). In hemangioblastomas and CC-RCCs, HIF-1alpha is constitutively overexpressed leading to increased transcription of HIF-1-regulated genes, including vascular endothelial growth factor (VEGF). Because loss of VHL function is associated with increased expression of the chemokine receptor CXCR4 in CC-RCCs, we investigated the expression of HIF-1alpha, CXCR4, and its ligand stromal cell-derived factor-1alpha (SDF-1alpha) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1alpha within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1alpha was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1alpha protein at levels that were significantly higher than those found in normal tissue. Analysis of the VHL-null RCC line 786-0 revealed that SDF-1alpha mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1alpha mRNA was significantly decreased in HIF-1alpha-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1alpha and CXCR4 protein expression confirmed the RNA findings in RCC lines and MEFs. These results suggest that loss-of-function of a single tumor suppressor gene can up-regulate the expression of both a ligand and its receptor, which may establish an autocrine signaling pathway with important roles in the pathogenesis of hemangioblastoma and CC-RCC.

Adenocarcinoma, Clear Cell↗

PubMed2006

Substitution of critical isoleucines in the KH domains of Drosophila fragile X protein results in partial loss-of-function phenotypes.

Fragile X mental retardation proteins (FMRP) are RNA-binding proteins that interact with a subset of cellular RNAs. Several RNA-binding domains have been identified in FMRP, but the contribution of these individual domains to FMRP function in an animal model is not well understood. In this study, we have generated flies with point mutations in the KH domains of the Drosophila melanogaster fragile X gene (dfmr1) in the context of a genomic rescue fragment. The substitutions of conserved isoleucine residues within the KH domains with asparagine are thought to impair binding of RNA substrates and perhaps the ability of FMRP to assemble into mRNP complexes. The mutants were analyzed for defects in development and behavior that are associated with deletion null alleles of dfmr1. We find that these KH domain mutations result in partial loss of function or no significant loss of function for the phenotypes assayed. The phenotypes resulting from these KH domain mutants imply that the capacities of the mutant proteins to bind RNA and form functional mRNP complexes are not wholly disrupted and are consistent with biochemical models suggesting that RNA-binding domains of FMRP can function independently.

Analysis of Variance↗

PubMed1998

[Functional hearing loss in children who were not aware of their hearing loss].

We investigated one hundred and fourteen ears of 60 children (8 males, 52 females, aged from 6 to 13 years) with diagnoses of functional hearing loss (FHL), and were not aware of their own hearing loss. Forty nine (81.7%) of 60 cases examined were detected by school screening tests, 6 (10.0%) were referred to our hospital because their families noticed poor hearing responses, and 5 (8.3%) were enrolled because they complained of otalgia or discomfort in the ear. Forty (66.7%) showed only pure tone threshold loss without complications, and the remaining 20 associated nonorganic disorders. In addition, our investigation found 11 cases (18.3%) with nonorganic otalgia, 5 (8.3%) with functional visual disturbance, 1 (1.7%) with enuresis nocturna who refused to attend school, 1 with tinnitus, 1 with vertigo, and 1 with tic. Moreover, 11 (18.3%) of the 60 cases were suspected of being in conflict with school and/or home. The Type V Békésy pattern, which is frequently observed in FHL and it has clinical utility to distinguish FHL from other types of organic hearing loss, was detected in 44 ears (38.6%). Fifty two (45.6%) of 114 ears showed normal pure-tone thresholds during the clinical course. Sixteen (14.0%) ears needed more than 1 year for thresholds to normalize. These findings suggest that some FHL cases without awareness of their hearing loss resemble psychogenic hearing loss. In such cases, otolaryngologists should carefully check the patient's individual circumstances, and when appropriate, refer patients for psychiatric consultation.

Adolescent↗

PubMed1995

Outcome following radiation treatment for high-risk pigmented villonodular synovitis.

PURPOSE: Pigmented villonodular synovitis (PVNS) is a rare proliferative process involving synovial membranes. It has a variable course, and while usually benign, may be destructive, resulting in major symptoms and loss of function leading to amputation. Optimum treatment is not always clear, and little information exists with respect to the role of radiotherapy. The purpose was to review our experience with radiotherapy in cases at high risk for recurrence with functional loss including instances where amputation was the sole alternative for symptomatic disease. METHODS AND MATERIALS: The records of all patients registered between 1972 and 1992 with a diagnosis of PVNS were identified (21 cases). The records of 14 cases who received radiotherapy after referral were reviewed retrospectively for demographic information, radiotherapy treatment parameters, and tumor outcome. RESULTS: All cases had confirmation of pathologic diagnosis. Six patients had primary and eight had recurrent disease (with a mean of 2.5 prior surgical procedures). All cases had both intra- and extraarticular disease and, without exception, the poorer prognosis diffuse subtype of the disease. The majority had one or more additional risk factors including skin, bone, tendon, neurovascular, or muscle group extension. With a mean follow-up time of 69 months (range 13-250 months), only one patient has shown persistence of disease. With the exception of that single case, all those with measurable disease had obvious disease until at least 12 months and, subsequently, manifested complete responses. The single case was lost from the clinic after 8 months from the initiation of radiotherapy to a dose of 30 Gy in 15 fractions and had a palpable mass at the time. He subsequently was noted to have a persisting mass and an excisional biopsy 9 years later showed PVNS. He remains well 21 years after treatment with good function. Eleven patients enjoyed excellent or good function from the affected limb and three had fair function. All patients had greater use of limb than at the time of treatment. No patient required amputation, and none had evidence of serious radiotherapy complications. CONCLUSIONS: These results demonstrate that moderate dose radiotherapy is an effective modality in the treatment of a subset of cases with this rare condition. Its use has permitted avoidance of amputation in very advanced cases with acceptable function preservation. When treatment is indicated we currently recommend gross total removal of PVNS. This is followed by moderate dose radiotherapy (35 Gy in 15 fractions) for residual disease where salvage of subsequent recurrence may compromise function.

Adolescent↗

PubMed1995

Proteinuria: a risk factor for pregnancy-related renal function decline in primary glomerular disease?

Pregnancy may be followed by a postpartum acceleration of renal function loss in patients with renal disease. We retrospectively analyzed the effects of pregnancy on progressive renal function decline, and the risk factors for an acceleration, in a group of 19 renal disease patients with 30 pregnancies and a group of 31 patients who did not become pregnant after onset of glomerular disease. The rate of renal function loss was calculated for each patient by linear regression on reciprocal serum creatinine values over 11 years' follow-up. Multiple regression analysis showed that both pregnancy (P = 0.03) and initial proteinuria (P = 0.005) were independently related with the rate of renal function loss. Such a relation could not be observed with histologic diagnosis, and initial age, renal function, blood pressure, and serum albumin. Further analysis showed that 10 of 30 pregnancies are followed by a predefined acceleration of renal function loss. These pregnancies were preceded and complicated by a higher proteinuria (4.1 v 1.7 g/d, P < 0.005; and 3.6 v 2.1 g/d, P < 0.05, respectively) compared with the other 20 pregnancies that are not followed by such an acceleration. In conclusion, patients with primary glomerular disease complicated by substantial proteinuria are at risk for acceleration of renal function decline after pregnancy.

Adolescent↗

PubMed1983

Functional visual loss. Follow-up of 42 cases.

Forty-two patients with diagnosed functional visual loss were reexamined an average of four years after their initial visit. Twenty-three patients continued to have constricted or spiral visual fields at follow-up. Despite persistent evidence of functional visual defects, few patients were either socially or economically impaired by them. Patients who had other types of visual field loss or loss of visual acuity were more likely to have these signs resolve than were patients with constricted or spiral fields. Concurrent unrelated organic ocular disease was present in 11 patients. In 20 patients, it was not possible to identify psychiatric symptoms either related to the onset of functional eye signs or at follow-up. Treatment did not substantially alter the course.

Adolescent↗

PubMed1998

Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A.

The AE1 gene encodes band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane. Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytosis. We report here novel AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D. AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A, rescued both AE1-mediated Cl- transport and AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.

Acidosis, Renal Tubular↗

PubMed2002

The "spray can" sign: validation of a clinical observation in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: The presentation of chronic inflammatory neuropathies is variable. The decision regarding when to intervene with treatment is ideally determined by identifying early markers of loss of function. OBJECTIVE: To test the hypothesis that an observation of functional impairment, defined by a patient with demyelinating neuropathy, can be used as a reproducible and reliable measure of improvement with intravenous immune globulin. DESIGN: A 28-year-old woman presented with a chronic inflammatory demyelinating polyneuropathy. Her first complaint was the inability to use her deodorant spray because of hand weakness. A calibrated pincer gauge fixed on top of her usual spray can was used to objectively test finger flexion. Tip grip and lateral pinch were also measured. A calibrated dynamometer was used to measure grip strength. RESULTS: Power and precision grip force were reproducible in normal control subjects by means of the spray can test. This test proved to be a reliable indicator of reduced muscle strength in the patient and improved after treatment with intravenous immune globulin. CONCLUSIONS: The spray can test objectively quantified the daily function, nominated by the patient, of operating an aerosol can. This measurement, drawn from a functional loss observed by the patient, proved to be a portable and reliable indicator of decline and recovery in chronic inflammatory demyelinating polyneuropathy.

Adult↗

PubMed2000

Blocking free radical production via adenoviral gene transfer decreases cardiac ischemia-reperfusion injury.

Periods of cardiac ischemia followed by reperfusion can lead to either transient loss of function (stunning) or permanent functional loss stemming from infarction, depending upon the length of the ischemic period. In either case the primary mediator of the injury may by oxygen-derived free radicals generated upon the reestablishment of blood flow. The heart's primary defense against peroxide, glutathione peroxidase, is depleted during ischemia. Thus, the ischemic myocardium might derive significant protection from increased levels of the enzyme, catalase, which can remove hydrogen peroxide in a redox-independent manner. To test these assertions, we studied the ability of adenoviral gene transfer to increase intracellular antioxidant activity via catalase expression. What we observed was that increasing catalase activity in the heart was sufficient to prevent the stunning associated with 15 min of ischemia followed by reperfusion.

Adenoviridae↗