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Results for “Loss of function”

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PubMed1991

The reaction of the guinea pig cochlea to perforations of the round window membrane with and without perilymph aspiration.

The influence of simple opening of the round window (RW) membrane and the effect of aspiration of perilymph on the electrophysiological characteristics of the cochlea was tested in guinea pigs by measurement of the compound action potentials. We found that perforations of the RW membrane failed to lead to either short-term or long-term damage in cochlear function. There was only a slight spontaneous escape of perilymph but without measurable functional loss. Additional aspiration of perilymph led to entry of air into the basal turn and to an immediate loss of function of the cochlea. This regressed within 4 weeks in the middle- and low-frequency ranges. Measurable long-term damage persisted only in the high-frequency ranges. We attribute contradictory results of other authors to methodological errors which we avoided by a specific selection of healthy animals and the development of standardized operation, recording and measurement procedures.

Acoustic Stimulation↗

PubMed2006

Chorein deficiency leads to upregulation of gephyrin and GABA(A) receptor.

Chorea-acanthocytosis (ChAc) is a hereditary neurodegenerative disorder caused by loss of function mutations in the VPS13A gene encoding chorein. Recently, using a gene-targeting technique to delete exons 60-61, we produced a ChAc-model mouse that corresponds to a human disease mutation. In this study, a comparative microarray analysis of gene expression in the striatum revealed an increased level of gephyrin gene expression in the ChAc-model mice compared with wild type mice. Since gephyrin is known as a GABA(A) receptor-anchoring protein, we compared the protein-level expression and localization of gephyrin and the GABA(A) receptor alpha1 (GABRA1) and gamma2 (GABRG2) subunits. Gephyrin and GABRG2 immunoreactivities in the striatum and hippocampus of the ChAc-model mice were significantly higher than those in the wild types. Our results suggest that chorein functional loss may lead to a compensatory upregulation of gephyrin and GABRG2 in the pathologic condition in ChAc.

Animals↗

PubMed2005

ClC-5: a chloride channel with multiple roles in renal tubular albumin uptake.

ClC-5 is a chloride (Cl(-)) channel expressed in renal tubules and is critical for normal tubular function. Loss of function nonsense or missense mutations in ClC-5 are associated with Dent's disease, a condition in which patients present with low molecular weight (LMW) proteinuria (including albuminuria), hypercalciuria and nephrolithiasis. Several key studies in ClC-5 knockout mice have shown that the proteinuria results from defective tubular reabsorption of proteins. ClC-5 is typically regarded as an intracellular Cl(-) channel and thus the defect in this receptor-mediated uptake pathway was initially attributed to the failure of the early endosomes to acidify correctly. ClC-5 was postulated to play a key role in transporting the Cl(-) ions required to compensate for the movement of H(+) during endosomal acidification. However, more recent studies suggest additional roles for ClC-5 in the endocytosis of albumin. ClC-5 is now known to be expressed at low levels at the cell surface and appears to be a key component in the assembly of the macromolecular complex involved in protein endocytosis. Furthermore, mutations in ClC-5 affect the trafficking of v-H(+)-ATPase and result in decreased expression of the albumin receptor megalin/cubulin. Thus, the expression of ClC-5 at the cell surface as well as its presence in endosomes appears to be essential for normal protein uptake by the renal proximal tubule.

Albumins↗

PubMed2004

Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica that cause typhoid.

Salmonella enterica serovars often have a broad host range, and some cause both gastrointestinal and systemic disease. But the serovars Paratyphi A and Typhi are restricted to humans and cause only systemic disease. It has been estimated that Typhi arose in the last few thousand years. The sequence and microarray analysis of the Paratyphi A genome indicates that it is similar to the Typhi genome but suggests that it has a more recent evolutionary origin. Both genomes have independently accumulated many pseudogenes among their approximately 4,400 protein coding sequences: 173 in Paratyphi A and approximately 210 in Typhi. The recent convergence of these two similar genomes on a similar phenotype is subtly reflected in their genotypes: only 30 genes are degraded in both serovars. Nevertheless, these 30 genes include three known to be important in gastroenteritis, which does not occur in these serovars, and four for Salmonella-translocated effectors, which are normally secreted into host cells to subvert host functions. Loss of function also occurs by mutation in different genes in the same pathway (e.g., in chemotaxis and in the production of fimbriae).

Base Sequence↗

PubMed1996

Risk factors for nursing home use after hospitalization for medical illness.

BACKGROUND: Hospitalization, a sentinel event for many older persons, may mark a transition from independent living to either community-based or institutionalized long-term care. We determined the independent risk factors, including loss of function, of nursing home (NH) admission at hospital discharge and NH use at 3 months after hospital discharge among a diverse group of hospitalized older persons. METHODS: The subjects in this study were 1,265 noninstitutionalized persons from phase II of Hospital Outcomes Project for the Elderly. Using multiple logistic regression, we modeled NH admission with variables measured at the time of hospital admission as well as with length of stay (LOS) and decline in ADL independence from hospital admission to discharge. In addition, we modeled NH use at 3 months after hospital discharge with variables measured at the time of hospital discharge as well as with post-hospital measures of rehospitalization and decline in ADL independence following hospitalization. RESULTS: The independence risk factors of NH placement at discharge are geographic site, increasing age, living alone, and low baseline ADL independence, LOS, and decline in ADL independence during hospitalization. The independent predictors for NH use at 3-month follow-up are increasing age, living alone, mental status, low discharge ADL independence, LOS, and decline in ADL independence during the 3 months after discharge. CONCLUSIONS: Simple but different clinical variables predict NH use at hospital discharge and at 3 months. Furthermore, functional loss during and after hospitalization is an important independent risk factor of nursing home use and is a clinical outcome that may be modified to decrease the likelihood of NH admission.

Activities of Daily Living↗

PubMed1982

Changes with age in renal function and morphology in C57BL/6, CBA/HT6, and B6CBAF1 mice.

Mice of the C57BL/6J and CBA/HT6J inbred strains and their F1 hybrid were investigated at 67, 202, 463, and 711 days of age to determine how genetic differences affected aging patterns of renal function and morphology. The three genotypes differed significantly in their body and kidney weights and their kidney to body weight ratios. These differences reflected functional capacities, and renal hypertrophy appeared to be an attempt to compensate for functional losses with age. The glomerular filtration rate (GFR) decreased in both inbred strains with age but remained constant in the F1 hybrid mice. There was a significant strain difference in GFR, but this difference disappeared when the GFR was considered in relation to the kidney weight. Thus the strain difference appeared to reflect differences in ability to compensate for loss of function by increasing kidney size. Osmolarities and sodium clearances decreased with age and increased with renal hypertrophy, but plasma levels were constant. Histopathological changes with age appeared to be correlated with functional changes.

Aging↗

PubMed2005

A loss-of-function mutation in AtYSL1 reveals its role in iron and nicotianamine seed loading.

The Arabidopsis Yellow Stripe 1-Like (YSL) proteins have been identified by homology with the maize (Zea mays) Yellow Stripe 1 (YS1) transporter which is responsible for iron-phytosiderophore (PS) uptake by roots in response to iron shortage. Although dicotyledonous plants do not synthesize PS, they do synthesize the PS precursor nicotianamine, a strong metal chelator essential for maintenance of iron homeostasis and copper translocation. Furthermore, ZmYS1 and the rice (Oryza sativa) protein OsYSL2 have metal-nicotianamine transport activities in heterologous expression systems. In this work, we have characterized the function of AtYSL1 in planta. Two insertional loss-of-function ysl1 mutants of Arabidopsis were found to exhibit increased nicotianamine accumulation in shoots. More importantly, seeds of both ysl1 knockouts contained less iron and nicotianamine than wild-type seeds, even when produced by plants grown in the presence of an excess of iron. This phenotype could be reverted by expressing the wild-type AtYSL1 gene in ysl1 plants. ysl1 seeds germinated slowly, but this defect was rescued by an iron supply. AtYSL1 was expressed in the xylem parenchyma of leaves, where it was upregulated in response to iron excess, as well as in pollen and in young silique parts. This pattern is consistent with long-distance circulation of iron and nicotianamine and their delivery to the seed. Taken together, our work provides strong physiological evidence that iron and nicotianamine levels in seeds rely in part on AtYSL1 function.

Arabidopsis↗

PubMed1986

Aphasia after stroke: natural history and associated deficits.

Data relating to 976 patients registered as suffering an acute stroke has been analysed to determine the natural history of speech disturbance: these patients came from a community survey of 215,000 people over a 28 month period. Of the 545 patients assessed within 7 days of stroke, 24% were aphasic and 28% unassessable. At 3 weeks, when over 90% of survivors were tested, 20% of those tested had aphasia. At 6 months only 12% of survivors had significant aphasia, but 44% of patients and 57% of carers thought speech was abnormal. Of those aphasic within 7 days, 40% remained so at 6 months; 60% of those aphasic at 3 weeks remained so. There was a high correlation between early and late aphasia scores. Aphasia was associated with more severe disability (degree of limb weakness, loss of function, loss of IQ), and with a less good recovery of social activities, but did not cause any measurable increase in stress upon carers. In a Health District of 250,000 people, about 60 patients each year may be referred for speech therapy after an acute stroke.

Acute Disease↗

PubMed1998

Pulmonary neuronal M2 muscarinic receptor function in asthma and animal models of hyperreactivity.

In the lungs neuronal M2 muscarinic receptors limit acetylcholine release from postganglionic cholinergic nerves. These inhibitory M2 receptors are dysfunctional in antigen challenged guinea pigs and in humans with asthma which leads to an increase in vagally mediated hyperreactivity. In vitro, eosinophil products act as allosteric antagonists at neuronal M2 muscarinic receptors. In vivo, displacing or neutralising MBP preserves neuronal M2 muscarinic receptor function and prevents hyperreactivity. Thus, there is good evidence from animal studies that after antigen challenge pulmonary M2 muscarinic receptors become dysfunctional because MBP inhibits their function. Loss of function of pulmonary neuronal M2 muscarinic receptors has also been reported in patients with asthma, although the clinical significance of this dysfunction and the mechanisms underlying it are not yet established.

Acetylcholine↗

PubMed2004

Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation.

Although melanocortin-4 receptor mutations are the cause of the most common monogenic form of obesity, the involvement of the melanocortin-3 receptor (MC3R) in the pathogenesis of obesity is unknown. Earlier studies failed to identify any mutations in obese patients except for the identification of two variants (K6T and I81V) that likely represent polymorphisms. However, a potential mutation (I183N) was recently reported from patients having high-fat contents. We report here the functional characterization of these variants. We show that K6T and I81V have ligand binding and signaling properties similar to wild-type (wt) MC3R, indicating that they are indeed polymorphisms. However, the other variant, I183N, completely lacks signaling in response to agonist stimulation, although it binds ligand with normal affinity and with only slightly decreased capacity. Coexpression of the wt and I183N MC3Rs showed that I183N does not exert dominant-negative activity on wt MC3R. These results provide supporting evidence for the hypothesis proposed in the original case report that MC3R mutation might be a genetic factor that confers susceptibility to obesity, likely due to haploinsufficiency. Further mutations at I183 revealed a discrete requirement for I183 in agonist-induced MC3R activation. The corresponding residue is also important for agonist-induced human melanocortin-4 receptor and lutropin receptor activation. In summary, we identify a residue that is critical for activation of G protein-coupled receptors.

Asparagine↗

PubMed2005

[Ureteral actinomycosis. Case report].

OBJECTIVES: To report one case of pseudotumoral lesion of the iliac ureter with obstructive uropathy leading to loss of function of the renal unit. METHODS: 66-year-old male being studied for BPH who presents with a self-limited monosymptomatic hematuria. RESULTS: Renal ultrasound detected grade II pyelocaliectasis of the right kidney. IVU showed absence of function of the right kidney. Urine cytology was consistent with low-grade transitional cell carcinoma. Percutaneous nephrostomy was performed confirming irreversible function loss. Antegrade pyelography showed a filling defect in the right iliac ureter. Radical nephroureterectomy with bladder cuff was carried out with good results. Pathology reported chronic pyelonephritis and parietal inflammatory lesion of the ureter obliterating the lumen with inflammatory infiltrates, urothelial erosion and presence of actinomyces. CONCLUSIONS: Actinomycosis is a chronic bacterial infection, with A. israeli being the most common pathogen. It is part of the normal flora of the oral cavity and GI tract, and cervical-facial region is the most frequent clinical involvement (60% of the cases). Urinary tract infection is exceptional. No other focus was found in the long-term follow-up.

Actinomycosis↗

PubMed2001

Fracture risk in patients with muscular dystrophy and spinal muscular atrophy.

We aimed at studying fracture risk in patients with Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy (BEMD), and spinal muscular atrophy type II and III (SMA II and III). A self-administered questionnaire was mailed to 293 patients with DMD, BEMD, SMA II or SMA III of which 229 returned the questionnaire. Each respondent was compared with an age- and gender-matched control subject. The mean age was 23.9 +/- 15.9 years for the patients and 23.3 +/- 16.5 years for the controls. There were significantly more fractures among patients than controls after the diagnosis was made (RR = 1.9), but not before. The patients had more fractures of the femurs, lower legs, and upper arms than the controls. Low energy fractures were more frequent in patients than controls (9% vs 0%). Many fractures in the femurs (40%), lower legs (35%), and feet and toes (44%) led to a permanent loss of function. Loss of ambulation was the major risk factor for fractures. In conclusion, fracture risk is increased in neuromuscular disease.

Adolescent↗

PubMed1991

The assessment and prediction of functional disability in rheumatoid arthritis.

We assessed functional disability with the Stanford Health Assessment Questionnaire Functional Disability Index (FDI) in 1,274 patients with rheumatoid arthritis (RA) followed longitudinally for up to 12 years. The rate of functional loss increased sharply after the first clinic visit. Half of patients with RA (median survival time) will reach FDI scores of about 1 in 2 years, 2 in 6 years, and 2.5 in 10 years after the first clinic visit, levels that correspond to moderate, severe and very severe loss of functional ability. Functional outcomes may be predicted by simple demographic and clinical assessments, the best of which are self-assessed measures of global severity, pain and function.

Adult↗

PubMed1984

Geriatric rehabilitation.

Elderly people experience motor, sensory and cognitive losses that affect their mobility and their ability to perform activities of daily living. There is often gradual loss of function, which requires recognition and correction. Sudden events, such as stroke, amputation or trauma, may occur in an environment of diminished function and reserve. Rehabilitation measures must be directed toward prevention of dysmobility, correction of functional losses and provision for continuing aftercare.

Activities of Daily Living↗

PubMed1998

Functional evaluation of the lung resection candidate.

Advances in operative technique and perioperative care have considerably reduced surgical morbidity and mortality after pulmonary resections. Various single and combined parameters of functional operability have been proposed to assess the surgical risk. Pulmonary function tests adequately assess the pulmonary risk, and baseline or stress electrocardiography, echocardiography and nuclear cardiac studies assess the cardiac risk. Patients with normal or only slightly impaired pulmonary function (forced expiratory volume in one second (FEV1) and transfer factor of the lung for carbon monoxide (TL,CO) > or = 80% of predicted) and no cardiovascular risk factors can undergo pulmonary resections up to a pneumonectomy without further investigation. For others, exercise testing, pulmonary split-function studies, or a combination of these two methods are recommended. Exercise testing, most frequently performed as a symptom-limited test with the measurement of maximal oxygen uptake (V'O2,max), assesses both the pulmonary and cardiovascular reserves. A V'O2,max of <10 mL.kg(-1).min(-1) is generally considered prohibitive for any resection, a value of >20 mL.kg(-1).min(-1) or >75% of predicted normal, safe for major resections. Split-function studies are radionuclide-based estimations of the predicted postoperative (ppo) values of various parameters. The currently used ppo-parameters are FEV1-ppo, TL,CO-ppo and, most recently, V'O2,max-ppo. Suggested cut-off values for safe resection are: for FEV1-ppo and TL,CO-ppo > or = 40% pred; and for V'O2,max > or = 35% pred, combined with an absolute value of > or = 10 mL.kg(-1).min(-1). The lowest acceptable ppo-values will still have to be established by additional prospective studies. In the long-term, resections involving not more than one lobe usually lead to an early functional deficit followed by later recovery. The permanent functional loss in pulmonary function is small (< or = 10%) and exercise capacity is only slightly reduced or not at all. Pneumonectomy, on the other hand, leads to an early permanent loss of about 33% in pulmonary function and 20% in exercise capacity. Thus, pulmonary function tests alone overestimate the functional loss after lung resection.

Exercise Test↗

PubMed2026

KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway.

Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. We combined clinical data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate pathways.KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In mice, KEAP1-deficient tumors exhibited accelerated growth and reduced DC and CD8+ T-cell infiltration, consistent with an immune-cold phenotype. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Genetic FSP1 deletion restored ferroptosis-associated immunogenicity and DC activation in KEAP1-deficient cells, supporting FSP1 as a potential therapeutic target for further in vivo evaluation.

DAMPs↗

PubMed2006

Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.

Elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) play a central role in the development of atherosclerosis. Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) that are associated with lower plasma levels of LDL-C confer protection from coronary heart disease. Here, we show that four severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wild-type PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the circulation and identified the first known individual who has no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for two inactivating mutations in PCSK9, had a strikingly low plasma level of LDL-C (14 mg/dL). The very low plasma level of LDL-C and apparent good health of this individual demonstrate that PCSK9 plays a major role in determining plasma levels of LDL-C and provides an attractive target for LDL-lowering therapy.

Adolescent↗

PubMed2006

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. OBJECTIVES: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. METHODS: We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. RESULTS: Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSION: Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. CLINICAL IMPLICATIONS: These findings underline the crucial role of the skin barrier in preventing allergic sensitization.

Case-Control Studies↗