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Results for “Loss of function”

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PubMed1991

[Formation of a neosphincter following loss of function of the upper esophageal sphincter].

In order to prevent aspiration following loss of function of the UOS a new sphincter may develop. This usually arises from the oblique part of the cricopharyngeus muscle and the caudal part of the thyropharyngeus muscle and it is functionally independent of the UOS. We examined 40 patients by cinematography: these included 30 patients with a Zenker's diverticulum, 8 patients following myotomy of the UOS and 2 patients with tumour infiltration of the UOS. The new sphincter could be demonstrated in 70% of patients with Zenker's diverticulum: its function depended on the size and localisation of the diverticulum. Following myotomy of the UOS the new sphincter is usually only just perceptible. In one case there was, however, marked dyskinesia, requiring further myotomy.

Adult↗

PubMed2025

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

PURPOSE: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. METHODS: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. RESULTS: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. CONCLUSION: We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

Humans↗

PubMed2006

Loss of function of COBRA, a determinant of oriented cell expansion, invokes cellular defence responses in Arabidopsis thaliana.

An Arabidopsis T-DNA insertion mutant that results in complete loss-of-function of the COBRA gene has been identified. The COBRA gene encodes a putative glycosylphosphatidylinositol (GPI)-anchored protein that modulates cellulose deposition and oriented cell expansion in roots. The loss-of-function mutant allele (named "cob-5") exhibits abnormal cell growth throughout the entire plant body and accumulates massive amounts of stress response chemicals such as anthocyanins and callose. To gain further insight into the mechanism by which COBRA affects cell growth and physiology, the whole-genome gene expression profile of cob-5 plants was compared with that of wild-type plants. Consistent with the mutant phenotype, many genes involved in anthocyanin biosynthesis were up-regulated in the cob-5 plants, whereas genes involved in cell elongation were down-regulated. The most striking feature of the gene expression profile of cob-5 was the massive and co-ordinate induction of defence- and stress-related genes, many of which are regulated by the plant stress signal jasmonic acid (JA). Indeed, the cob-5 plants over-accumulated JA by nearly 8-fold compared with wild-type plants. Furthermore, induction of cell elongation defects in conditional allele cob-3 plants triggers the expression of a defence-responsive gene. These results provide potential clues to the mechanisms by which plant cells initially perceive biotic stress at the cell surface.

Arabidopsis↗

PubMed2006

Genome-scale loss-of-function screening with a lentiviral RNAi library.

The discovery that RNA interference (RNAi) is functional in mammalian cells led us to form The RNAi Consortium (TRC) with the goal of enabling large-scale loss-of-function screens through the development of genome-scale RNAi libraries and methodologies for their use. These resources form the basis of a loss-of-function screening platform created at the Broad Institute. Our human and mouse libraries currently contain >135,000 lentiviral clones targeting 27,000 genes. Initial screening efforts have demonstrated that these libraries and methods are practical and powerful tools for high-throughput lentivirus RNAi screens.

Animals↗

PubMed1996

Heterotopic splenic autotransplantation in a neonate with splenic rupture, leading to normal splenic function.

Loss of the spleen in infants and young children frequently results in overwhelming infection. To preserve splenic function, heterotopic splenic autotransplantation after splenectomy was performed on a newborn in whom the spleen was traumatized beyond repair because of birth trauma. Postoperatively, the percentage of pitted red blood cells that accurately reflects splenic reticuloendothelial function was normal. Splenic scintigrams obtained 3 weeks after the operation showed uptake by the reimplanted tissue. The otherwise mandatory long-term antibiotic prophylaxis could be reduced to 3 weeks in the newborn. At 7 years of age, the patient has not shown any increased susceptibility to infections.

Antibiotic Prophylaxis↗

PubMed2006

RCAS-RNAi: a loss-of-function method for the developing chick retina.

BACKGROUND: The embryonic chick provides an excellent model system for studies of development. However, it has lacked an efficient loss-of-function method for studies of gene function. RESULTS: We show that avian retroviruses can deliver hairpins mediating RNA interference to the developing chick eye. These viruses 'knock down' specific genes in infected areas of the retina. The knock down persists as the retina matures and can be detected using in situ hybridization. Furthermore, the amount of retinal tissue affected can be controlled by manipulating the degree of infection. CONCLUSION: This technique provides a rapid and efficient loss-of-function option for studies in the developing chick retina.

Animals↗

PubMed1995

Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells.

Signals transduced by the met tyrosine kinase, which is the receptor for scatter factor/hepatocyte growth factor, are of major importance for the regulation of epithelial cell motility, morphogenesis, and proliferation. We report here that different sets of tyrosine residues in the cytoplasmic domain of the met receptor affect signal transduction in epithelial cells in a positive or negative fashion: mutation of the C-terminal tyrosine residues 13-16 (Y1311, Y1347, Y1354, and Y1363) reduced or abolished ligand-induced cell motility and branching morphogenesis. In contrast, mutation of the juxtamembrane tyrosine residue 2 (Y1001) produced constitutively mobile, fibroblastoid cells. Furthermore, the gain-of-function mutation of tyrosine residue 2 suppressed the loss-of-function mutations of tyrosine residue 15 or 16. The opposite roles of the juxtamembrane and C-terminal tyrosine residues may explain the suggested dual function of the met receptor in both epithelial-mesenchymal interactions and tumor progression.

Amino Acid Sequence↗

PubMed1998

Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome.

Nail-patella syndrome (NPS) is an inherited developmental disorder most commonly involving maldevelopment of the fingernails, kneecaps and elbow joints. NPS exhibits wide variation in phenotypic expression within and among families with respect to these features. Other skeletal abnormalities such as hip dislocation and club foot have also been reported in some individuals with NPS. There is an association between NPS and renal disease, and between NPS and open-angle glaucoma (OAG), but it is not known whether mutations in a single gene cause the observed skeletal, renal and ophthalmic abnormalities. Recently, LMX1B , a transcription factor of the LIM-homeodomain type with homologs that are important for limb development in vertebrates, was mapped to the same general location as NPS at 9q34. We sequenced a large segment of LMX1B from the genomic DNA of probands from four families with NPS and OAG, and identified four mutations: two stop codons, a deletion causing a frameshift and a missense mutation in a functionally important residue. The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicates that haploinsufficiency of LMX1B underlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development. The results further suggest that the NPS and OAG phenotypes in the families studied result from mutations in a single gene, LMX1B.

Adolescent↗

PubMed1994

Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux.

The yeast (Saccharomyces cerevisiae) PDR5 gene product encodes a 160-kDa protein related to the large ABC family of transporters, including the human MDR1 multidrug resistance p-glycoprotein. Loss of function mutations in PDR5 result in chloramphenicol hypersensitivity. A pdr5::Tn5 loss of function mutant exhibits a markedly impaired efflux of chloramphenicol compared with that of an isogenic PDR5 (wild-type) control.

ATP-Binding Cassette Transporters↗

PubMed2004

Intraspecific mating with CzechII/Ei mice rescue lethality associated with loss of function mutations of the imprinted genes, Igf2r and Cdkn1c.

Maternal inheritance of targeted loss of function alleles encoding either the cyclin-dependent kinase inhibitor 1C (Cdkn1c) or the insulin-like growth factor 2 receptor (Igf2r) leads to fully penetrant perinatal lethality in C57BL/6J mice due to genomic imprinting. Here, we demonstrate that there is a marked enhancement in postnatal viability of F(1) mice carrying either the ablated Igf2r ( approximately 32%) or Cdkn1c ( approximately 83%) when the paternal genome was derived from the inbred Mus musculus musculus CzechII/Ei strain. Genetic and molecular analyses indicated that the increased viability was not caused by relaxation of imprinted gene expression, but is the consequence of unidentified polygenic modifiers that are not imprinted. In the course of this study, restriction-site polymorphisms between 129S1 and CzechII/Ei in 21 imprinted and 14 biallelically expressed genes were identified. These polymorphisms may prove useful in determining the effects of different mutant backgrounds on genomic imprinting.

Alleles↗

PubMed1986

Functional visual loss in children.

Twenty-three children (16 girls, 7 boys, aged 6-17 years) who presented with the specific complaint of blurred vision were diagnosed as having functional visual loss. Symptoms were intermittent in seven children. Associated signs and symptoms were common and included headaches, visual field loss, diplopia, micropsia, voluntary nystagmus, and spasm of the near reflex. Our treatment consisted of reassurance and follow-up. Resolution of symptoms occurred within 24 hours in one third and within two months in three-quarters of our patients. Parental support and encouragement were associated with more rapid resolution. Recurrence of symptoms and late onset of somatic complaints were rare. Conflicts related to family or school environment were common. Four children had been sexually or physically abused. Our experience suggests that, regardless of the duration or severity of symptoms, functional visual loss in children can usually be treated with reassurance. We believe that psychiatric referral is not necessary for most patients. Sexual or physical abuse should be considered as a possible predisposing factor.

Adolescent↗

PubMed2001

Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor.

Activation by melanocortins of the melanocortin 1 receptor (MC1R), expressed in epidermal melanocytes, stimulates melanogenesis. Human MC1R gene loss-of-function mutations are associated with fair skin, poor tanning and increased skin cancer risk. We identified two natural alleles: Ile40Thr, probably associated with skin types I-II, and Val122Met. Val122Met bound [(125)I][Nle(4), D-Phe(7)]-alpha-melanocyte stimulating hormone with lower affinity than the wild-type. Dose-response curves of cAMP accumulation were right-shifted for both forms. The Val122Met form failed to achieve maximal cAMP responses comparable to the wild-type or Ile40Thr receptors. Thus, the Ile40Thr and Val122Met variants are partial loss-of-function natural mutations of MC1R.

Alleles↗

PubMed2004

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant.

Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of one glutamic acid in the carboxyl terminus of a protein named torsinA. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wild-type protein. Although there is increasing evidence that dysfunction of the dopamine system is implicated in the development of EOTD, the biological function of torsinA and its relation to dopaminergic neurotransmission has remained unexplored. Here, we show that torsinA can regulate the cellular trafficking of the dopamine transporter, as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsinA. The dystonia-associated torsinA deletion mutant (DeltaE-torsinA) did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in DeltaE-torsinA reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of wild-type torsinA through a mechanism presumably involving association of wild-type and mutant torsinA. Taken together, our results provide evidence for a functional role for torsinA and a loss of function and a dominant-negative phenotype of the DeltaE-torsinA mutation. These properties may contribute to the autosomal dominant nature of the condition.

Adenosine Triphosphate↗

PubMed2006

Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.

BACKGROUND: Childhood eczema often precedes the development of asthma and allergic rhinitis in the so-called atopic march. Recently, 2 loss-of-function mutations in the gene encoding the epidermal barrier protein filaggrin were reported to be predisposing factors for eczema and concomitant asthma, suggesting a possible role in disease transition. OBJECTIVE: We aimed to assess the importance of filaggrin loss-of-function mutations in the susceptibility to eczema and associated clinical phenotypes. METHODS: The filaggrin mutations were genotyped and tested for association with allergic disorders in 2 large European populations including 1092 children with eczema. RESULTS: Highly significant association of the filaggrin null mutations with eczema and concomitant asthma was replicated. Moreover, we found that these mutations predispose to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema. We show that the presence of 2 filaggrin null alleles is an independent risk factor for asthma in children with eczema, and that the 2 investigated mutations account for about 11% of eczema cases in the German population. CONCLUSION: These results lend strong support to the role of filaggrin in the pathogenesis of eczema and in the subsequent progression along the atopic march. The fact that previous expression of eczema is a prerequisite for the manifestation of allergic airways disease and specific sensitization highlights the importance of the epidermal barrier in the pathogenesis of these disorders. CLINICAL IMPLICATIONS: Our results suggest that the maintenance and repair of the epidermal barrier in infants with eczema may prevent the subsequent development of allergic airways disease.

Asthma↗

PubMed2006

Characterization of loss-of-function and gain-of-function Eph receptor tyrosine kinase signaling in C. elegans axon targeting and cell migration.

To understand how our brains function, it is necessary to know how neurons position themselves and target their axons and dendrites to their correct locations. Several evolutionarily conserved axon guidance molecules have been shown to help navigate axons to their correct target site. The Caenorhabditis elegans Eph receptor tyrosine kinase (RTK), VAB-1, has roles in early neuroblast and epidermal cell movements, but its roles in axon guidance are not well understood. Here, we report that mutations that disrupt the VAB-1 Eph receptor tyrosine kinase cause incompletely penetrant defects in axonal targeting and neuronal cell body positioning. The predominant axonal defect in vab-1 mutant animals was an overextension axon phenotype. Interestingly, constitutively active VAB-1 tyrosine kinase signaling caused a lack of axon outgrowth or an early termination phenotype, opposite to the loss-of-function phenotype. The combination of loss-of-function and gain-of-function analyses suggests that the VAB-1 Eph RTK is required for targeting or limiting axons and neuronal cells to specific regions, perhaps by transducing a repellent or stop cue.

Animals↗

PubMed2000

Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked syndrome characterized by pre- and postnatal overgrowth (gigantism), which clinically resembles the autosomal Beckwith-Wiedemann syndrome (BWS). Deletions and translocations involving the glypican-3 gene ( GPC3 ) have been shown to be associated with SGBS. Occasionally, these deletions also include the glypican-4 gene ( GPC4 ). Glypicans are heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. We have examined the mutational status of the GPC3 and GPC4 genes in one patient with Perlman syndrome, three patients with overgrowth without syndrome diagnosis, ten unrelated SGBS-patients and 11 BWS patients. We identified one SGBS patient with a deletion of a GPC3 exon. Six SGBS patients showed point mutations in GPC3. One frameshift, three nonsense, and one splice mutation predict a loss-of-function of the glypican-3 protein. One missense mutation, W296R, changes an amino acid that is conserved in all glypicans identified so far. A GPC3 protein that reproduces this mutation is poorly processed and fails to increase the cell surface expression of heparan sulfate, suggesting that this missense mutation is also a loss-of-function mutation. In three SGBS patients and in all non-SGBS patients, no mutations could be identified. We found three single nucleotide polymorphisms in the GPC4 gene but no evidence for loss-of-function mutations in GPC4 associated with SGBS.

Amino Acid Sequence↗

PubMed2005

Noncanonical Wnt-4 signaling and EAF2 are required for eye development in Xenopus laevis.

Wnt-4 is expressed in developing neural and renal tissue and is required for renal tubulogenesis in mouse and Xenopus. The function of Wnt-4 in neural differentiation is unknown so far. Here we demonstrate that Wnt-4 is required for eye development in Xenopus laevis. This effect of Wnt-4 depends on the activation of a beta-catenin-independent, noncanonical Wnt signaling pathway. Furthermore, we report the identification of EAF2, a component of the ELL-mediated RNA polymerase II elongation factor complex, as a target gene of Wnt-4 signaling. EAF2 is specifically expressed in the eye and EAF2 expression was dependent on Wnt-4 function. Loss of EAF2 function results in loss of eyes and loss of Wnt-4 function could be rescued by EAF2. In neuralized animal caps, EAF2 has properties characteristic for an RNA polymerase II elongation factor regulating the expression of the eye-specific transcription factor Rx. These data add a new layer of complexity to our understanding of eye development and give further evidence for the importance of noncanonical Wnt pathways in organ development.

Amino Acid Sequence↗

PubMed2002

[Laron syndrome by loss of functions of growth hormone receptor].

Laron syndrome, characterized by a short stature with raised serum levels of growth hormone but extremely low levels of insulin-like growth factor I, is caused by genetic defects of growth hormone receptor, including loss of functions of growth hormone receptor and abnormal growth hormone receptor acting in a dominant negative manner. This chapter focused on loss of functions of growth hormone receptor causing disruption of growth hormone binding and intracellular signalling. Most mutations and deletions have been found in extracellular domains of growth hormone receptor. Serum levels of growth hormone binding protein, cleaved from the extracellular portion of the growth hormone receptor, are typically decreased in most patients but are normal or high in some patients.

Dwarfism, Pituitary↗