Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemophilia A and B are X-linked disorders which are due to a reduced activity of coagulation factor VIII or IX, respectively. Female carriers have a wide range of plasma concentration of factor VIII or factor IX, and may in rare cases have an affected phenotype. In order to investigate if this variation is related to X chromosome inactivation, we determined the X inactivation pattern in 31 haemophilia A and 15 haemophilia B carriers, using a PCR in the androgen receptor locus in blood DNA. Seven of the haemophilia A carriers and none of the haemophilia B carriers had a skewed pattern (> or =80:20). One of the skewed haemophilia A carriers had a low plasma concentration of factor VIII (0.15 U/ml), but the remaining 6 carriers did not differ in factor VIII concentration from that of carriers with a random X inactivation pattern. One carrier with a high factor VIII concentration (2.0 U/ml) did not have a skewed pattern. Similarly, for the haemophilia B carriers, there was no tendency to a more skewed X inactivation pattern in the carriers with low or high factor IX concentrations. In addition, we analysed a female with haemophilia B who was heterozygous for the mutation R180W in the factor IX gene. She had a random X chromosome inactivation pattern. We conclude that the wide range in plasma concentration of factor VIII and factor IX in haemophilia A and B carriers cannot in general be explained by the X chromosome inactivation pattern in peripheral blood cells.
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PMID:Absence of correlation between X chromosome inactivation pattern and plasma concentration of factor VIII and factor IX in carriers of haemophilia A and B. 1074 50

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.
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PMID:Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. 1083 43

Hemophilia A is a X-linked bleeding disorder that is caused by the functional absence of blood coagulation factor VIII. The bleeding tendency in hemophilia A patients can be corrected by the administration of plasma-derived or recombinant factor VIII concentrates. A serious complication in hemophilia care is the development of factor VIII neutralizing antibodies (inhibitors) that arise as a consequence of factor VIII replacement therapy. The majority of factor VIII inhibitors are directed toward epitopes located within the A2, A3, and C2 domains of factor VIII. In this article, we summarize current knowledge on the epitope specificity of factor VIII inhibitors. In addition, we will discuss recent information on the molecular characteristics of human anti-factor VIII antibodies generated by phage display technology.
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PMID:Phage display technology: a tool to explore the diversity of inhibitors to blood coagulation factor VIII. 1091 6

The development of anti-factor VIII and anti-factor IX allo-antibodies in haemophilia A and B, respectively, remains a serious complication of treatment for these two X-linked haemostatic disorders, with major clinical and economic consequences. Treatment of this potentially fatal complication remains one of the greatest challenges facing haematologists at the beginning of the 21st century. Immune tolerance induction (ITI) therapy has been generally accepted as the best available treatment, extinguishing the inhibitor and permitting a resumption of standard dosing schedules. Although there have been several established protocols for ITI therapy developed over the last quarter century, the optimal scheme in terms of safety, clinical efficacy and pharmacoeconomic considerations has yet to be determined.
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PMID:Immune tolerance therapy for haemophilia. 1103 Apr 66

Hemophilia is an X-linked bleeding diathesis caused by a deficiency of either factor VIII or factor IX. Present treatment for hemophilia involves intravenous infusion of either recombinant or plasma-derived clotting factor concentrates. Problems with this treatment method, including the expense, need for intravenous access, and risks of blood-borne disease transmission, have fueled an interest in developing a gene-transfer approach to treatment. On the basis of experience with protein concentrate therapy, it seems likely that even modest elevations in circulating levels of factor VIII or factor IX can prevent most of the mortality and much of the morbidity associated with the disease. Hemophilia has a number of advantages as a model system for working out strategies for gene transfer as an approach to the treatment of genetic diseases; these include wide latitude in choice of target tissue, a wide therapeutic window for levels of circulating factor, ease of determining therapeutic endpoints, and existence of excellent animal models of the disease. Preclinical studies over the last decade have recently culminated in the initiation of clinical trials of gene transfer for hemophilia A and B. Three trials, each using different vectors and target tissues, are presently underway, and two additional trials are in late planning stages. This report reviews the preclinical data underlying these strategies and the design of the ongoing and proposed clinical trials.
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PMID:Gene transfer as an approach to treating hemophilia. 1115 64

Hemophilia A and B are X-linked bleeding disorders caused by mutations within the factor VIII and factor IX genes, respectively. Although both disorders can be easily treated by substitution with concentrates of functional factor VIII and factor IX, considerable effort has been undertaken to develop a gene therapy for hemophilia in order to improve patients' life quality and reduce high costs of therapy. The principle of gene therapy is the introduction of an intact copy of the factor VIII/factor IX gene in somatic cells, compensating for the defective gene. To do this, retroviral, adenoviral, and adeno-associated virus (AAV) vector systems, among others, were used. Encouraged by the results of preliminary experiments using preponderant mouse and canine models, three clinical phase I studies on hemophilia A and B patients have been initiated, one of which has been preliminarily reported successful.
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PMID:Gene therapy of hemophilia. 1154 64

Haemophilia A is a X-linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are "private", because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype-phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated.
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PMID:Seven novel and four recurrent point mutations in the factor VIII (F8C) gene. 1174 50

Haemophilia A is a X-linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are "private", because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype-phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated.
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PMID:Seven novel and four recurrent point mutations in the factor VIII (F8C) gene. 1175 15

Haemophilia A is the commonest cause of X-linked inherited bleeding disorder. Due to inadequate medical facility for management of the disease, the DNA based genetic diagnosis has assumed great importance. Ideally, the direct detection of mutations is the most accurate and reliable approach for carrier detection and prenatal diagnosis. However, mutation detection is possible only in limited number of cases. In majority of haemophiliacs, no common mutation is easily identifiable. The limitation has been over come by the use of linkage-based analysis using polymorphic DNA markers in the factor VIII gene. Some of these markers can be identified by restriction enzymes and are called RFLP markers. Other markers are a class of short tandem repeats sequences which result in differences in the number of CA repeats in different individuals. The combined use of these markers has made it possible to identify carriers and provide prenatal diagnosis in upto 95% of families having affected individuals. Therefore, the recurrence of the disease can be prevented to a great extent in the haemophilia A affected families.
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PMID:Molecular diagnosis in haemophilia A. 1183 49

Anderson Fabry Disease (AFD) is an extremely painful and debilitating multi-system X-linked disorder due to alpha-galactosidase enzyme deficiency. To date, no baseline data on health-related quality-of-life (HR-QoL) have been reported in males affected with this condition. In this study, 38 males with AFD completed Medical Outcomes Study Short Form, EuroQoL questionnaires and an AFD-specific questionnaire prior to the start of a trial involving replacement therapy with alpha-galactosidase. Results from these questionnaires were compared to the results from a similar HR-QoL study in males with severe haemophilia (factor VIII/IX deficiency) that used the same questionnaires and to the results of two large normative studies. The results on both questionnaires showed that in most instances males with AFD recorded significantly lower HR-QoL compared with males in the general population and individuals with severe haemophilia after adjusting for differences in age. These findings suggest therefore, that the scope for improvement in HR-QoL as a result of treatment with an appropriate agent is extremely large.
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PMID:Assessment of health-related quality-of-life in males with Anderson Fabry Disease before therapeutic intervention. 1201 36


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