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At least 289 records · Page 16Linked to original sources
PubMed2003

DX-88 and HAE: a developmental perspective.

An example of an approach to the developmental philosophy of novel recombinant products is explored by using the exemplar of Hereditary Angioedema (HAE). Plasma kallikrein is believed to be an important mediator of angioedema in patients with genetic deficiency of C1 esterase inhibitor (HAE patients). DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein which in early clinical studies demonstrates a useful efficacy/safety ratio in the treatment of acute attacks of HAE.

Acute Disease↗
PubMed2003

Lec3 Chinese hamster ovary mutants lack UDP-N-acetylglucosamine 2-epimerase activity because of mutations in the epimerase domain of the Gne gene.

Lec3 Chinese hamster ovary (CHO) cell glycosylation mutants have a defect in sialic acid biosynthesis that is shown here to be reflected most sensitively in reduced polysialic acid (PSA) on neural cell adhesion molecules. To identify the genetic origin of the phenotype, genes encoding different factors required for sialic acid biosynthesis were transfected into Lec3 cells. Only a Gne cDNA encoding UDP-GlcNAc 2-epimerase:ManNAc kinase rescued PSA synthesis. In an in vitro UDP-GlcNAc 2-epimerase assay, Lec3 cells had no detectable UDP-GlcNAc 2-epimerase activity, and Lec3 cells grown in serum-free medium were essentially devoid of sialic acid on glycoproteins. The Lec3 phenotype was rescued by exogenously added N-acetylmannosamine or mannosamine but not by the same concentrations of N-acetylglucosamine, glucosamine, glucose, or mannose. Sequencing of CHO Gne cDNAs identified a nonsense (E35stop) and a missense (G135E) mutation, respectively, in two independent Lec3 mutants. The G135E Lec3 mutant transfected with a rat Gne cDNA had restored in vitro UDP-GlcNAc 2-epimerase activity and cell surface PSA expression. Both Lec3 mutants were similarly rescued with a CHO Gne cDNA and with CHO Gne encoding the known kinase-deficient D413K mutation. However, cDNAs encoding the known epimerase-deficient mutation H132A or the new Lec3 G135E Gne mutation did not rescue the Lec3 phenotype. The G135E Gne missense mutation is a novel mechanism for inactivating UDP-GlcNAc 2-epimerase activity. Lec3 mutants with no UDP-GlcNAc 2-epimerase activity represent sensitive hosts for characterizing disease-causing mutations in the human GNE gene that give rise to sialuria, hereditary inclusion body myopathy, and Nonaka myopathy.

Amino Acid Sequence↗
PubMed2003

Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia.

Mmutations in paraplegin, a putative mitochondrial metallopeptidase of the AAA family, cause an autosomal recessive form of hereditary spastic paraplegia (HSP). Here, we analyze the function of paraplegin at the cellular level and characterize the phenotypic defects of HSP patients' cells lacking this protein. We demonstrate that paraplegin coassembles with a homologous protein, AFG3L2, in the mitochondrial inner membrane. These two proteins form a high molecular mass complex, which we show to be aberrant in HSP fibroblasts. The loss of this complex causes a reduced complex I activity in mitochondria and an increased sensitivity to oxidant stress, which can both be rescued by exogenous expression of wild-type paraplegin. Furthermore, complementation studies in yeast demonstrate functional conservation of the human paraplegin-AFG3L2 complex with the yeast m-AAA protease and assign proteolytic activity to this structure. These results shed new light on the molecular pathogenesis of HSP and functionally link AFG3L2 to this neurodegenerative disease.

ATP-Dependent Proteases↗
PubMed1991

Periodontal disease mechanisms in immunocompromised patients.

Deficiency in the number and function of phagocytes is associated with gingival inflammation and periodontitis. A hereditary deficiency in membrane glycoproteins involved in granulocyte adherence causes impaired chemotaxis, reduced phagocytosis and periodontal problems. Virus infections of antigen-presenting cells interfere with immune responses and lead to seriously increased susceptibility to infections with bacteria which cause no problems in normal patients. Increased levels of IgG antibodies may limit penetration of antigens in the tissues, but at the cost of local inflammation and tissue injury. Mucosal inflammatory disease with increased local formation of IgG is more frequent in IgA deficient patients. The immunological homeostasis depends on a balance between the respective classes and subclasses of antibodies. Deficiencies in the IgA system may contribute to a disturbed balance of the humoral immune response to critical antigens from oral bacteria. A disproportional increase in IgG1 and IgG3 antibodies may persistently activate complement, stimulate the inflammatory activity and cause tissue injury.

Humans↗
PubMed1979

Acquired C1 esterase inhibitor deficiency and angioedema: a review.

A case of acquired C1INH deficiency with angioedema is described. Fifteen cases are thus far recorded. The clinical syndrome of angioedema in these patients closely resembles hereditary angioedema (HAE). Most cases are associated with a paraprotein, cryoglobulin, or autoantibody, which presumably initiates C1 activation and C1 Inhibitor consumption. C1INH, C4 and C2 levels are low in acquired C1INH deficiency, as in HAE. A distinguishing feature is that C1 titers are very low in the acquired disease and only minimally depressed, if at all, in HAE. Most cases have appeared in patients with an underlying lymphoproliferative or autoimmune disease. Therapy is directed at the underlying disorder, but androgen therapy may be helpful in preventing attacks. Future potential therapeutic approaches are discussed.

Angioedema↗
PubMed1990

[Hereditary angioneurotic edema. Management in pediatric surgery].

Hereditary angioneurotic oedema is an autosomal dominant disorder associated with serum deficiency of functionally active C1 inhibitor protein (type 1) or normal serum level of functionally deficient C1-inhibitor (type 2). These biochemical abnormalities induce a complement activation which leads to episodic swelling of interstitial tissues usually of the abdominal viscera and of the upper airway with resultant asphyxia. Vasoactive peptides from the degradation of component C2 of the complement along with an activation of basophils by chemotactic substances from the degradation of C3 and C5 are the main mechanisms involved in vasodilatation and swelling. Attacks of angioneurotic oedema, sometimes fatal when involving the upper airway, can occur during any but usually during ear-throat-nose, dental or facial surgery. This article describes the pathophysiology and the main features of the disease in children. It reviews the different treatments used to avoid attacks or to cure an attack of angio-oedema once it has begun, both during planed surgery and during emergency surgery.

Adolescent↗
PubMed2005

Basic and clinical immunology.

The authors selected articles published in the literature from January 2004 through December 2004 that were relevant to the areas of basic and clinical immunology. Several articles explored the development of TH1 or TH2 response and the role of the monocyte-T cell interaction. Others were articles describing the action of drugs commonly used in asthma to inhibit cytokine responses and the anti-inflammatory role of nonimmune pulmonary cells present in the lung. Several reports show how dendritic cells are being developed as vehicles for DNA vaccines aimed at stimulating cellular responses, an advance of great importance for HIV researchers working on vaccines, who are concerned about the different ways HIV evades the immune response. Other publications described Toll-like receptors in diverse cells, including mast cells and CD4+ T cells, for the recognition of viruses and bacteria. In the area of clinical immunology, an updated classification for primary immunodeficiencies with more than 100 identified genes responsible for these diseases and the report on the second clinical trial of gene therapy for X-linked severe combined immunodeficiency syndrome were published. Significant advances included the clinical prognosis in common variable immunodeficiency for patients presenting with lung pathology, the safety of live vaccines in partial DiGeorge syndrome, the report of patients with complete DiGeorge syndrome with the presence of peripheral blood T cells, the clinical spectrum of patients with NF-kappaB essential modifier (NEMO) gene deficiency, the publication of a consensus algorithm for the management of hereditary angioedema, and the report of immune restoration syndrome in pediatric HIV infection.

Animals↗
PubMed2004

Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast.

Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, DeltaF508, leads to nearly complete degradation via endoplasmic reticulum-associated degradation (ERAD). Elucidation of the quality control and degradation mechanisms might give rise to new therapeutic approaches to cure this disease. In the yeast Saccharomyces cerevisiae, a variety of components of the protein quality control and degradation system have been identified. Nearly all of these components share homology with mammalian counterparts. We therefore used yeast mutants defective in the ERAD system to identify new components that are involved in human CFTR quality control and degradation. We show the role of the lectin Htm1p in the degradation process of CFTR. Complementation of the HTM1 deficiency in yeast cells by the mammalian orthologue EDEM underlines the necessity of this lectin for CFTR degradation and highlights the similarity of quality control and ERAD in yeast and mammals. Furthermore, degradation of CFTR requires the ubiquitin protein ligases Der3p/Hrd1p and Doa10p as well as the cytosolic trimeric Cdc48p-Ufd1p-Npl4p complex. These proteins also were found to be necessary for ERAD of a mutated yeast "relative" of CFTR, Pdr5(*)p.

Adenosine Triphosphatases↗
PubMed1989

[Indicators of nonspecific immunity in patients with hereditary hemochromatosis].

Parameters of nonspecific defence--complement protein function, circulating immune complex level, neutrophil phagocytic activity, completeness of the phagocytic reaction, C3c level, were evaluated in 162 carriers of hemochromatosis gene (114 homozygotes and 48 heterozygotes with respect to hereditary hemochromatosis) aged from 7 to 64 years. The analysis of the results obtained has permitted a conclusion that the suppression of the complement system function, according to the classic or alternative type, is associated with the disease pathogenesis--hyperferremia, and is caused by the damage of the immunocompetent organs and cells synthesizing individual proteins of the complement, as well as by infectious complications leading to hypocomplementemia with respect to separate components.

Adolescent↗
PubMed2004

PEX1 deficiency presenting as Leber congenital amaurosis.

Peroxisome biogenesis disorders result from defects in peroxin proteins involved in peroxisomal matrix and membrane protein import. Peroxins are encoded in peroxin protein genes; to date, the PEX genes responsible for all 12 peroxisome biogenesis disorders complementation groups are known. Peroxin protein 1 deficiency associated with complementation group 1 is responsible for disease in approximately two thirds of all patients with a peroxisome biogenesis disorder. Their phenotypes range from severe to mild, and it appears to be a phenotype-genotype relationship. This case report describes a patient with peroxin protein 1 deficiency presenting as Leber congenital amaurosis, in whom the diagnosis was questioned at the age of 2 years when seizures first appeared and mild facial dysmorphia became evident.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1992

Inherited defects in DNA repair and susceptibility to DNA-damaging agents.

Since all organisms are continuously exposed to exogenous and endogenous DNA damaging agents, mechanisms of repair of DNA lesions are necessary to maintain the integrity of the genome. Studies of the cellular defects in human inherited diseases with deficiencies in DNA repair have given new insights into these processes. Nucleotide excision repair is an important DNA repair pathway in which several types of DNA lesions are removed by a multi-step enzymatic process. This repair mechanism is deficient in the rare disease xeroderma pigmentosum (XP), which results in extreme sensitivity to ultraviolet light (UV) and development of UV-induced skin tumors at an early age. There are several genetic complementation groups of XP. The genes that are mutated in some of the XP complementation groups have been cloned and the functions of the encoded proteins are being characterised. Several types of DNA lesions are removed more rapidly from active genes than from other regions of DNA. This preferential repair of active genes is deficient in Cockayne's syndrome, which is characterised by developmental abnormalities and UV-sensitivity but no marked increase in cancer incidence. Other syndromes associated with increased sensitivity to certain DNA damaging agents where no defect in DNA repair has been defined include Fanconi's anemia (sensitivity to DNA cross-linking agents), hereditary dysplastic nevus syndrome (sensitivity to UV) and ataxia-telangiectasia (sensitivity to ionizing radiation).

Ataxia Telangiectasia↗
PubMed2002

Current management of hereditary angio-oedema (C'1 esterase inhibitor deficiency).

Hereditary angio-oedema is characterised by recurrent swellings in any part of the body and also by recurrent attacks of severe abdominal pain. The disease is inherited in an autosomal dominant manner but up to 25% of cases can occur as a spontaneous mutation. Attacks of swelling can be precipitated by trauma, certain drugs, and emotional stress. Treatment usually involves a combination of prophylaxis, using androgens or antifibrolytic drugs, and replacement with C'1 esterase inhibitor concentrate for acute attacks and before surgery or other traumatic procedures.

Acute Disease↗
PubMed2002

Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy.

A G to A transition at nucleotide 11778 in the ND4 subunit gene of complex I was the first point mutation in the mitochondrial genome linked to a human disease. It causes Leber Hereditary Optic Neuropathy, a disorder with oxidative phosphorylation deficiency. To overcome this defect, we made a synthetic ND4 subunit compatible with the "universal" genetic code and imported it into mitochondria by adding a mitochondrial targeting sequence. For detection we added a FLAG tag. This gene was inserted in an adeno-associated viral vector. The ND4FLAG protein was imported into the mitochondria of cybrids harboring the G11778A mutation, where it increased their survival rate threefold, under restrictive conditions that forced the cells to rely predominantly on oxidative phosphorylation to produce ATP. Since assays of complex I activity were normal in G11778A cybrids we focused on changes in ATP synthesis using complex I substrates. The G11778A cybrids showed a 60% reduction in the rate of ATP synthesis. Relative to mock-transfected G11778A cybrids, complemented G11778A cybrids showed a threefold increase in ATP synthesis, to a level indistinguishable from that in cybrids containing normal mitochondrial DNA. Restoration of respiration by allotopic expression opens the door for gene therapy of Leber Hereditary Optic Neuropathy.

Adenosine Triphosphate↗
PubMed2005

Deficiencies of C1 inhibitor.

Hereditary and acquired deficiencies of the C1 inhibitor result in a single prominent symptom, namely angioedema. Angioedema may involve the skin, the gastrointestinal tract or the upper airway. Genetically determined defects in C1INH cause hereditary angioedema. The defect may be acquired as the result of an auto-antibody to C1INH or be due to the generation of anti-idiotypic antibody to monoclonal immunoglobulins as occurs in various B cell lymphoproliferative diseases. Androgens provide prophylaxis against attacks of angioedema. There is no widely approved treatment for acute attacks of angioedema although several promising drugs are now in the final stages of clinical trials.

Angioedema↗
PubMed1994

[Angioneurotic edema and anesthesia: preparation and perioperative monitoring].

Hereditary angioneurotic oedema is an autosomal dominant disease associated with serum deficiency of functional C1-inhibitor. It is characterized by periodic swelling of subcutaneous tissues, abdominal viscera and upper airways. Lethal acute episodes of oedema can occur during anaesthesia and surgery. It is essential to prepare such patients before surgery. This article describes three cases (kidney transplantation, caesarean section, normal delivery) and the various preventive measures used to avoid acute episodes during anaesthesia and surgery. Antibrinolytic agents, androgens, fresh frozen plasma, C1-inhibitor concentrate can be administered. Their various indications are discussed.

Adult↗
PubMed1992

Hormonally exacerbated hereditary angioedema.

Hereditary angioedema is a rare disorder which is associated with an inherited deficiency of the inhibitor of the activated first component of complement. Genetic transmission occurs in an autosomal dominant manner. Affected patients are heterozygotes, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor. We describe two cases of C1 esterase inhibitor deficiency occurring in a mother and daughter in whom the symptoms appeared to be related to the menstrual cycle or the taking of the oral contraceptive pill. Although both features have been mentioned in the literature, to the best of our knowledge premenstrual exacerbations have not been documented previously. We examined the likely basis of hormonally exacerbated hereditary angioedema.

Adolescent↗
PubMed1984

Cleavage of C2 in pathological serum and plasma studied by crossed immunoelectrophoresis.

A cleavage product of C2, C2a was demonstrated by crossed immunoelectrophoresis in serum and EDTA plasma from patients with active systemic lupus erythematosus (SLE), patients in the early phase of acute poststreptococcal glomerulonephritis (AGN), and from two males with congenital deficiency of C1(-) inactivator, one of whom had symptoms of hereditary angioedema. C2a was not found in normal serum and plasma. C2 was more stable in plasma than in serum with regard to the effects of storage in room temperature and of repeated freezing and thawing. C2a concentrations were higher in serum than in plasma samples from SLE and AGN patients. Expressed in per cent of the total C2 protein, C2a was inversely correlated (r = -0.91) with the C2 hemolytic activity in the samples, which explains discrepancies between the results of immunochemical and functional assays, when used to measure C2 concentrations in disease.

Adult↗
PubMed1989

[New possibilities of treating acute angioedema caused by C1-inhibitor deficiency].

The authors discuss diagnostic difficulties in 12 cases of hereditary angioneurotic edema due to C1-esterase inhibitor (C1-INH deficiency). Emphasis is on the treatment of the acute attacks with intravenous infusions of C1-inhibitor concentrate (Boehring, West Germany). This proved to be a very efficient and safe therapy, leading to a prompt disappearance of all clinical symptoms. Throughout 12 months following the infusions, indices of the liver function remained within the normal range, and anti-Hbs and anti-HIV tests were negative.

Acute Disease↗