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Results for “Loss of function”

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PubMed1989

The coincidence of myocardial reperfusion injury and hydrogen peroxide production in the isolated rat heart.

To investigate the specific nature and timing of oxygen (O2) metabolite reperfusion injury, we used a rat-heart model (Langendorff's solution, 37 degrees C) and hydrogen peroxide (H2O2)-dependent aminotriazole inactivation of catalase as a measure of myocardial H2O2 before, during, and after ischemia. We found that after ischemia (20 minutes, global, 37 degrees C), ventricular functional loss--as assessed by measurement of developed pressure (DP), +dp/dt, and -dp/dt with a ventricular balloon--occurred at 10 minutes of reperfusion and that myocardial H2O2 production was maximal by this time. Furthermore, H2O2 production did not occur during ischemia, and inhibition of xanthine oxidase by tungsten feeding or infusing a permeable O2 metabolite scavenger during reperfusion (dimethylthiourea) prevented ventricular functional loss. We conclude that (1) reperfusion injury is in part mediated by toxic oxygen metabolites, (2) H2O2 is the central O2 metabolite responsible for reperfusion injury, and (3) the timing of H2O2 production coincides with the timing of ventricular functional loss.

Amitrole↗

PubMed1992

Selective loss of functional antidonor cytolytic T cell precursors following donor-specific blood transfusions in long-term renal allograft recipients.

Pretransplant administration of donor-specific blood transfusions prolongs the survival of HLA-disparate renal allografts to a level comparable to that of HLA-identical transplants. To test the hypothesis that DST recipients develop immunologic tolerance of their donors, we examined antidonor T cell immunity in a group of DST recipients with long-term well-functioning allografts. Limiting dilution analysis studies indicated that 5/14 long-term DST recipients exhibit a complete absence of detectable antidonor cytolytic T lymphocyte precursors (CTLp). In contrast, 4/4 long-term non-DST recipients who received conventional or cyclosporine immunosuppression exhibited significant levels of antidonor CTLp. Nonresponsive DST recipients retained the capacity to mount antidonor responses in mixed lymphocyte reactions and IL-2 production assays, and exhibited normal levels of CTLp directed to third-party antigens. Addition of exogenous IL-2 to cell-mediated lympholysis cultures did not restore antidonor CTL responses. In summary, our data suggest that the DST conditioning regimen induces a complete yet selective loss of functional antidonor CTLp in some long-term renal transplant recipients.

Blood Transfusion↗

PubMed2002

Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia.

We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-func-tion with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin.

Adenosine Triphosphatases↗

PubMed1998

Local application of collagen containing brain-derived neurotrophic factor decreases the loss of function after spinal cord injury in the adult rat.

We studied the effect of local application of brain-derived neurotrophic factor (BDNF) on functional recovery after dorsal spinal cord transection in the adult rat. BDNF was applied at the site of the lesion in rat tail collagen type I. Locomotion was measured for 4 weeks using the BBB locomotor rating scale. One day after injury and application of BDNF the performance of treated rats was significantly increased as compared to controls (BBB-score 11.5+/-1.3 (mean +/- SEM) and 7.5+/-1.3, respectively). This difference remained significant during the first week. Histological examination of the spared spinal cord tissue at the lesion centre 4 weeks after lesioning showed no significant difference between control and BDNF-treated animals. The results indicate that local application of BDNF results in a decreased loss of function in the partially transected rat spinal cord starting one day after injury.

Animals↗

PubMed2000

Type I hyperlipoproteinemia due to a novel loss of function mutation of lipoprotein lipase, Cys(239)-->Trp, associated with recurrent severe pancreatitis.

Lipoprotein lipase (LPL) is the major enzyme responsible for the hydrolysis of triglyceride-rich lipoproteins in plasma. The purpose of this study was to examine the molecular pathogenesis of type I hyperlipoproteinemia in a patient suffering from recurrent severe pancreatitis. Apolipoprotein (apo) CII concentration was normal as well as apo CII-activated LPL in an in vitro assay. In postheparin plasma neither LPL mass nor activity was detectable, whereas hepatic lipase activity was normal. Direct sequencing of all 10 exons of the LPL gene revealed that the patient was homozygous for a hitherto unknown mutation in exon 6, Cys(239)-->Trp. The mutation prevents the formation of the second disulfide bridge of LPL, which is an essential part of the lid covering the catalytic center. Consequently, misfolded LPL is rapidly degraded within the cells, causing the absence of LPL immunoreactive protein in the plasma of this patient. In conclusion, we have identified a novel loss of function mutation in the LPL gene (Cys(239)-->Trp) of a patient with type I hyperlipoproteinemia suffering from severe recurrent pancreatitis. After initiation of heparin therapy (10,000 U/day sc), the patient experienced no more episodes of pancreatitis, although heparin therapy did not affect serum triglyceride levels.

Amino Acid Substitution↗

PubMed2005

Loss-of-function mutations in chitin responsive genes show increased susceptibility to the powdery mildew pathogen Erysiphe cichoracearum.

Chitin is a major component of fungal walls and insect exoskeletons. Plants produce chitinases upon pathogen attack and chito-oligomers induce defense responses in plants, though the exact mechanism behind this response is unknown. Using the ATH1 Affymetrix microarrays consisting of about 23,000 genes, we examined the response of Arabidopsis (Arabidopsis thaliana) seedlings to chito-octamers and hydrolyzed chitin after 30 min of treatment. The expression patterns elicited by the chito-octamer and hydrolyzed chitin were similar. Microarray expression profiles for several genes were verified via northern analysis or quantitative reverse transcription-PCR. We characterized T-DNA insertion mutants for nine chito-oligomer responsive genes. Three of the mutants were more susceptible to the fungal pathogen, powdery mildew, than wild type as measured by conidiophore production. These three mutants included mutants of genes for two disease resistance-like proteins and a putative E3 ligase. The isolation of loss-of-function mutants with enhanced disease susceptibility provides direct evidence that the chito-octamer is an important oligosaccharide elicitor of plant defenses. Also, this study demonstrates the value of microarray data for identifying new components of uncharacterized signaling pathways.

Arabidopsis↗

PubMed2001

Loss-of-function mutations in yjbD result in ClpX- and ClpP-independent competence development of Bacillus subtilis.

Mutations in clpP and clpX have pleiotropic effects on growth and developmentally regulated gene expression in Bacillus subtilis. ClpP and ClpX are needed for expression of comK, encoding the competence transcription factor required for the expression of genes within the competence regulon. ClpP, in combination with the ATPase ClpC, degrades the inhibitor of ComK, MecA. Proteolysis of MecA is stimulated by a small protein, ComS, which interacts with MecA. Suppressor mutations (cxs) were isolated that bypass the requirement for clpX for comK expression. These were found also to overcome the defect in comK expression conferred by a clpP mutation. These mutations were identified as missense mutations (cxs-5, -7 and -12) and a nonsense (UAG) codon substitution (cxs-10) in the yjbD coding sequence in a locus linked to mecA. That a yjbD disruption confers the cxs phenotype, together with its complementation by an ectopically expressed copy of yjbD, indicated that the suppressor alleles bear recessive, loss-of-function mutations of yjbD. ClpP- and ClpX-independent comK expression rendered by inactivation of yjbD was still medium-dependent and required ComS. MecA levels in a clpP-yjbD mutant were lower that those of clpP mutant cells and ComK protein concentration in the clpP mutant was restored to wild-type levels by the yjbD mutation. Consequently, the yjbD mutation bypasses the defect in competence development conferred by clpP and clpX. YjbD protein is barely detectable in wild-type cells, but is present in large amounts in the clpP mutant cells. The results suggest that the role of ClpP in competence development is to degrade YjbD protein so that ComS can productively interact with the MecA-ClpC-ComK complex. Alternatively, the result could suggest that YjbD has a negative effect on regulated proteolysis and that MecA is degraded independently of ClpP when YjbD is absent.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1998

Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission. The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete CSNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel alpha1-subunit genes. Mutation analysis of this new alpha1-subunit gene, CACNA1F, in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation. These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina.

Amino Acid Sequence↗

PubMed1998

Mutation in the pleckstrin homology domain of the human phospholipase C-delta 1 gene is associated with loss of function.

The delta-type phospholipase C (PLC) is thought to be evolutionally the most basal form in the mammalian PLC family. One of the delta-type isoforms, PLC-delta 1, binds to both phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) with a high affinity via its pleckstrin homology (PH) domain. We report here a missense mutation in the region encoding the C-terminal PH domain of the human PLC-delta 1. This is also the first report of a mutation in the human PLC genes. A single base substitution (G to A) causes the amino acid replacement, Arg105 to His. Site-directed mutagenesis of the glutathione-S-transferase (GST)/PLC-delta 1 fusion protein changing Arg105 to His resulted in a fourfold decrease in the affinity of specific Ins(1,4,5)P3 binding and a reduction in PtdIns(4,5)P2 hydrolysing activity to about 40% of that of the wild-type enzyme. This remarkable loss of function can be interpreted in terms of a conformational change in the PH domain.

Blood Proteins↗

PubMed1999

Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a group of heterogeneous disorders of unknown origin, usually inherited as an autosomal recessive trait. Its phenotype is characterized by axonemal abnormalities of respiratory cilia and sperm tails leading to bronchiectasis and sinusitis, which are sometimes associated with situs inversus (Kartagener syndrome) and male sterility. The main ciliary defect in PCD is an absence of dynein arms. We have isolated the first gene involved in PCD, using a candidate-gene approach developed on the basis of documented abnormalities of immotile strains of Chlamydomonas reinhardtii, which carry axonemal ultrastructural defects reminiscent of PCD. Taking advantage of the evolutionary conservation of genes encoding axonemal proteins, we have isolated a human sequence (DNAI1) related to IC78, a C. reinhardtii gene encoding a dynein intermediate chain in which mutations are associated with the absence of outer dynein arms. DNAI1 is highly expressed in trachea and testis and is composed of 20 exons located at 9p13-p21. Two loss-of-function mutations of DNAI1 have been identified in a patient with PCD characterized by immotile respiratory cilia lacking outer dynein arms. In addition, we excluded linkage between this gene and similar PCD phenotypes in five other affected families, providing a clear demonstration of locus heterogeneity. These data reveal the critical role of DNAI1 in the development of human axonemal structures and open up new means for identification of additional genes involved in related developmental defects.

Amino Acid Sequence↗

PubMed2000

Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects.

All vertebrates display a characteristic asymmetry of internal organs with the cardiac apex, stomach and spleen towards the left, and the liver and gall bladder on the right. Left-right (L-R) axis abnormalities or laterality defects are common in humans (1 in 8,500 live births). Several genes (such as Nodal, Ebaf and Pitx2) have been implicated in L-R organ positioning in model organisms. In humans, relatively few genes have been associated with a small percentage of human situs defects. These include ZIC3 (ref. 5), LEFTB (formerly LEFTY2; ref. 6) and ACVR2B (encoding activin receptor IIB; ref. 7). The EGF-CFC genes, mouse Cfc1 (encoding the Cryptic protein; ref. 9) and zebrafish one-eyed pinhead (oep; refs 10, 11) are essential for the establishment of the L-R axis. EGF-CFC proteins act as co-factors for Nodal-related signals, which have also been implicated in L-R axis development. Here we identify loss-of-function mutations in human CFC1 (encoding the CRYPTIC protein) in patients with heterotaxic phenotypes (randomized organ positioning). The mutant proteins have aberrant cellular localization in transfected cells and are functionally defective in a zebrafish oep-mutant rescue assay. Our findings indicate that the essential role of EGF-CFC genes and Nodal signalling in left-right axis formation is conserved from fish to humans. Moreover, our results support a role for environmental and/or genetic modifiers in determining the ultimate phenotype in humans.

Abnormalities, Multiple↗

PubMed1999

Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.

Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with deficiency of cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain. To investigate to what extent SURF-1 is responsible for human disorders because of COX deficiency, we undertook sequence analysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defective patients classified as having typical Leigh syndrome (LS(COX)), 6 patients classified as Leigh-like (LL(COX)) cases, and 16 patients classified as non-LS(COX) cases. Frameshift, stop, and splice mutations of SURF-1 were detected in 18 of 24 (75%) of the LS(COX) cases. No mutations were found in the LL(COX) and non-LS(COX) group of patients. Rescue of the COX phenotype was observed in transfected cells from patients harboring SURF-1 mutations, but not in transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis. Loss of function of SURF-1 protein is specifically associated with LS(COX), although a proportion of LS(COX) cases must be the result of abnormalities in genes other than SURF-1. SURF-1 is the first nuclear gene to be consistently mutated in a major category of respiratory chain defects. DNA analysis can now be used to accurately diagnose LS(COX), a common subtype of Leigh syndrome.

Child, Preschool↗

PubMed2007

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.

OBJECTIVE: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. DESIGN: Mutational analysis of MC2R by direct sequencing. PATIENTS: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). RESULTS: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. CONCLUSIONS: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.

Adrenal Insufficiency↗

PubMed2006

Loss of function polymorphisms in NAT1 protect against spina bifida.

Periconceptional folic acid supplementation reduces the risk of having a child with spina bifida. N-acetyltransferase 1 (NAT1) participates in the catabolism of folates and the acetylation of aromatic and heterocyclic amines. Hence, functional polymorphisms in NAT1, the gene encoding NAT1, could influence the risk of spina bifida via either folate catabolism or acetylation of exogenous agents. Individuals with spina bifida and their parents were genotyped for six NAT1 single nucleotide polymorphisms (SNPs) for which the less common allele is associated with reduced or absent enzyme activity (i.e. 97C>T, 190C>T, 559C>T/560G>A, 640T>G and 752A>T). In addition, a "composite" NAT1 genotype was defined as a function of the genotyped SNPs. Descriptive analyses of the SNPs and of the composite genotype indicated that heterozygous parents were more likely to transmit the common allele than the rare allele to their affected offspring. Furthermore, matings of mothers homozygous for the common allele and heterozygous fathers were more common than the reciprocal matings. Log-linear analyses confirmed that both the maternal (P = 0.008) and offspring (P = 0.003) composite NAT1 genotypes were significantly related to the risk of spina bifida. NAT1 variants that reduce or abolish enzyme activity appear to protect against spina bifida, and to exert their influence via both the maternal and the offspring genotypes. These associations may be attributable to a decrease in either folate catabolism or the conversion of exogenous agents to teratogenic derivatives in women and/or developing embryos with a NAT1 genotype that includes a loss of function allele relative to those who do not.

Adult↗

PubMed1994

Acoustic reflex threshold tenth percentiles and functional hearing impairment.

This study addressed the issue of whether functional impairments can be identified or confirmed using tonal acoustic reflex thresholds (ARTs). Tonal ARTs from 74 ears with functional impairments were compared to 10th percentiles of the ARTs for normal and cochlear-impaired ears at 500 to 2000 Hz (Gelfand, Schwander, and Silman, 1990). Only one ear (5.3%) was correctly identified among the 19 ears in which all of the voluntary thresholds at 500 to 2000 Hz were < or = 55 dB HL. Acoustic reflex thresholds correctly identified functional losses in 70.9 percent, 78.6 percent, and 85.7 percent of the ears with voluntary thresholds > or = 60 dB HL at one, two, or three of these frequencies, respectively. The false positive rate was only 5 to 7 percent for a control group of 50 ears with genuine sensorineural hearing losses. The results indicate that tonal ARTs are an effective nonbehavioral tool for identifying or substantiating the presence of functional losses when thresholds are > or = 60 dB HL; however, ARTs cannot identify functional components when thresholds are < or = 55 dB HL.

Acoustic Stimulation↗

PubMed2000

A strong loss-of-function mutation in RAN1 results in constitutive activation of the ethylene response pathway as well as a rosette-lethal phenotype.

A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resulted in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a competitive inhibitor of ethylene binding. In contrast to the previously identified ran1-1 and ran1-2 alleles that are morphologically indistinguishable from wild-type plants, this ran1-3 allele results in a rosette-lethal phenotype. The predicted protein encoded by the RAN1 gene is similar to the Wilson and Menkes disease proteins and yeast Ccc2 protein, which are integral membrane cation-transporting P-type ATPases involved in copper trafficking. Genetic epistasis analysis indicated that RAN1 acts upstream of mutations in the ethylene receptor gene family. However, the rosette-lethal phenotype of ran1-3 was not suppressed by ethylene-insensitive mutants, suggesting that this mutation also affects a non-ethylene-dependent pathway regulating cell expansion. The phenotype of ran1-3 mutants is similar to loss-of-function ethylene receptor mutants, suggesting that RAN1 may be required to form functional ethylene receptors. Furthermore, these results suggest that copper is required not only for ethylene binding but also for the signaling function of the ethylene receptors.

Alleles↗

PubMed2005

Localization and loss-of-function implicates ciliary proteins in early, cytoplasmic roles in left-right asymmetry.

Left-right asymmetry is a crucial feature of the vertebrate body plan. While much molecular detail of this patterning pathway has been uncovered, the embryonic mechanisms of the initiation of asymmetry, and their evolutionary conservation among species, are still not understood. A popular recent model based on data from mouse embryos suggests extracellular movement of determinants by ciliary motion at the gastrulating node as the initial step. An alternative model, driven by findings in the frog and chick embryo, focuses instead on cytoplasmic roles of motor proteins. To begin to test the latter hypothesis, we analyzed the very early embryonic localization of ciliary targets implicated in mouse LR asymmetry. Immunohistochemistry was performed on frog and chick embryos using antibodies that have (KIF3B, Polaris, Polycystin-2, acetylated alpha-tubulin) or have not (LRD, INV, detyrosinated alpha-tubulin) been shown to detect in frog embryos only the target that they detect in mammalian tissue. Immunohistochemistry revealed localization signals for all targets in the cytoplasm of cleavage-stage Xenopus embryos, and in the base of the primitive streak in chick embryos at streak initiation. Importantly, several left-right asymmetries were detected in both species, and the localization signals were dependent on microtubule and actin cytoskeletal organization. Moreover, loss-of-function experiments implicated very early intracellular microtubule-dependent motor protein function as an obligate aspect of oriented LR asymmetry in Xenopus embryos. These data are consistent with cytoplasmic roles for motor proteins in patterning the left-right axis that do not involve ciliary motion.

Animals↗

PubMed2005

A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse.

The achondroplastic mouse is a spontaneous mutant characterized by disproportionate dwarfism with short limbs and tail due to disturbed chondrogenesis during endochondral ossification. These abnormal phenotypes are controlled by an autosomal recessive gene (cn). In this study, linkage analysis using 115 affected mice of F2 progeny mapped the cn locus on an approximately 0.8-cM region of chromosome 4, and natriuretic peptide receptor 2 (Npr2) gene was identified as the most potent candidate for the cn mutant in this region. This gene encodes a receptor for C-type natriuretic peptide (CNP) that positively regulates longitudinal bone growth by producing cGMP in response to CNP binding to the extracellular domain. Sequence analyses of the Npr2 gene in cn/cn mice revealed a T to G transversion leading to the amino acid substitution of highly conserved Leu with Arg in the guanylyl cyclase domain. In cultured chondrocytes of cn/cn mice, stimulus with CNP did not significantly increase intracellular cGMP concentration, whereas it increased in +/+ mice. Transfection of the mutant Npr2 gene into COS-7 cells also showed similar results, indicating that the missense mutation of the Npr2 gene in cn/cn mice resulted in disruption of the guanylyl cyclase activity of the receptor. We therefore concluded that the dwarf phenotype of cn/cn mouse is caused by a loss-of-function mutation of the Npr2 gene, and cn/cn mouse will be a useful model to further study the molecular mechanism regulating endochondral ossification by CNP/natriuretic peptide receptor B signal.

Achondroplasia↗