Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O75695 (X-linked recessive)
 2,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycerol kinase deficiency (GKD) is an X-linked recessive disorder. There are two types. an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life-threatening childhood metabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC-GKD-DMD or AHC-GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, I nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic variability of the isolated GKD was remarkable. The clinical variability in isolated GKD cannot be explained by biochemical or by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.
 ...
PMID:Isolated and contiguous glycerol kinase gene disorders: a review. 1103 29

Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by the absence of a muscle cytoskeletal protein, dystrophin. Utrophin is the autosomal homologue of dystrophin. We previously demonstrated that overexpression of utrophin in the muscles of dystrophin-null transgenic mice completely prevented the phenotype arising from dystrophin deficiency. Two independently regulated promoters control utrophin expression and the upstream promoter (promoter A) is synaptically regulated in muscle. In this study, we have investigated basal regulation and myogenic induction of promoter A. Interactions between Ap2 and Sp1 and their cognate DNA motifs are critical for basal transcription from the minimal promoter region. During differentiation of C2C12 myoblasts in vitro, a 2-fold increase in A-utrophin mRNA level was observed. Expression of a reporter gene, whose transcription was driven by a 1.3 kb promoter A fragment, paralleled expression of the endogenous transcript. Myogenic induction mapped to a conserved upstream muscle-specific E-box, which was shown to bind myogenic regulatory factors, transactivating the promoter up to 18-fold in transient assays. This study provides a basis for further understanding the regulatory mechanisms that control utrophin expression in muscle and may facilitate the development of reagents to effect therapeutic up-regulation of utrophin in DMD.
 ...
PMID:The role of basal and myogenic factors in the transcriptional activation of utrophin promoter A: implications for therapeutic up-regulation in Duchenne muscular dystrophy. 1172 94

Duchenne muscular dystrophy (DMD), the severe X-linked recessive disorder which results in progressive muscle degeneration, is due to a lack of dystrophin, a membrane cytoskeletal protein. Three types of treatment are envisaged: pharmacological (glucocorticoid), myoblast transplantation, and gene therapy. An alternative to the pharmacological approach is to compensate for dystrophin loss by the upregulation of another cytoskeletal protein, utrophin. Utrophin and dystrophin are part of a complex of proteins and glycoproteins, which links the basal lamina to the cytoskeleton, thus ensuring the stability of the muscle membrane. One protein of the complex, syntrophin, is associated with a muscular isoform of the neuronal nitric oxide synthase (nNOS). We have demonstrated an overexpression of utrophin, visualised by immunofluorescence and quantified by Western blotting, in normal myotubes and in mdx (the animal model of DMD) myotubes, as in normal (C57) and mdx mice, both treated with nitric oxide (NO) donor or L-arginine, the NOS substrate. There is evidence that utrophin may be capable of performing the same cellular functions as dystrophin and may functionally compensate for its lack. Thus, we propose to use NO donors, as palliative treatment of Duchenne and Becker muscular dystrophies, pending, or in combination with, gene and/or cellular therapy. Discussion has focussed on the various isoforms of NOS that could be implicated in the regeneration process. Dystrophic and healthy muscles respond to treatment, suggesting that although NOS is delocalised in the cytoplasm in the case of DMD, it conserves substantial activity. eNOS present in mitochondria and iNOS present in cytoplasm and the neuromuscular junction could also be activated. Lastly, production of NO by endothelial NOS of the capillaries would also be beneficial through increased supply of metabolites and oxygen to the muscles.
 ...
PMID:Muscular nitric oxide synthase (muNOS) and utrophin. 1175 82

Duchenne muscular dystrophy is a severe life-threatening X-linked recessive disorder, caused by mutations in the dystrophin gene, for which currently there is no effective treatment. Because of the large size of the dystrophin cDNA (14 kb) this precluded it from being used in early adenovirus- or retrovirus-based gene therapy vectors. However, some therapeutic success has been achieved in mdx mice using adenovirus- and retrovirus-mediated transfer of a 6.3 kb recombinant mini-dystrophin cDNA. Despite this, problems with immunogenicity and inefficient transduction of mature myofibres make these vectors less than ideal for gene transfer to skeletal muscle. Adeno-associated viral (AAV) vectors overcome many of the problems associated with other vector systems. However, AAV vectors can only accommodate <5 kb of foreign DNA. For this reason we have produced a micro-dystrophin cDNA gene construct that is <3.8 kb. This construct, driven by a CMV promoter, was introduced into the skeletal muscle of 12-day-old nude/mdx mice using an AAV vector, resulting in specific sarcolemmal expression of micro-dystrophin in >50% of myofibres up to 20 weeks of age, and effective restoration of the dystrophin-associated protein (DAP) complex components. Additionally, evaluation of central nucleation indicated a significant inhibition of degenerative dystrophic muscle pathology. We have therefore shown that the current micro-dystrophin gene delivered in vivo using an AAV vector is not only capable of restoring sarcolemmal DAP complexes, but can also ameliorate dystrophic pathology at the cellular level.
 ...
PMID:Adeno-associated virus vector gene transfer and sarcolemmal expression of a 144 kDa micro-dystrophin effectively restores the dystrophin-associated protein complex and inhibits myofibre degeneration in nude/mdx mice. 1192 46

Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene. A large intragenic deletion has been described in about 65% of DMD/BMD patients. Mothers of affected males are DMD/BMD carriers in two thirds of the cases. Routine deletions detection in DMD/BMD males is performed using multiplex polymerase chain reaction (mPCR), RT-PCR with a protein truncation test (PTT) or using Southern blotting. In females the deletions detection is complicated by the presence of a normal gene copy on the second X-chromosome. We are presenting the diagnostic strategy using FISH for the deletions detection in the dystrophin gene of female DMD/BMD carriers. We have used a set of six cosmid probes for the detection of the most frequently deleted areas of the dystrophin gene from the Department of Human Genetics, Leiden University Medical Center. We have examined 14 mothers of DMD/BMD males with a deletion in the dystrophin gene identified using mPCR. Four mothers of affected males have been diagnosed as carriers of a deletion in the dystrophin gene. We have revealed no deletion mutations in the exons examined in a control group of four healthy females. No discrepancy has been found between the FISH analysis results and the results of mPCR. Our results indicate that FISH is an effective and direct method for the identification of DMD/BMD carriers and we suggest this method as a method of a first choice in the identification of DMD/BMD carriers.
 ...
PMID:[Detection of carriers of Duchenne and Becker muscular dystrophy using the fluorescence in situ hybridization method]. 1193 57

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive genetic disorders resulting from mutations in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5' and central region of the gene. The remaining DMD/BMD cases show no deletions, so they cannot be easily identified by current strategies. In these DMD/BMD families, a linkage analysis that involves DNA markers of the flanking and intragenic dystrophin gene are necessary for carrier and prenatal diagnosis. We analyzed eighteen deletion-prone exons of the gene by a polymerase chain reaction (PCR) in order to characterize the molecular defects of the dystrophin gene in Korean DMD/BMD families. We also performed a linkage analysis to assess the usefulness and application of six short tandem repeat markers for molecular diagnosis in the families. We observed a deletion that eliminated the exon 50. Also, a linkage analysis in the families with six short tandem repeat (STR) markers showed heterozygosity at most of the STR markers. The haplotype analysis was useful for detecting the carrier status. This study will be helpful for a molecular diagnosis of DMD/BMD families in the Korean population.
 ...
PMID:Molecular diagnosis of Duchenne/Becker muscular dystrophy by polymerase chain reaction and microsatellite analysis. 1213 77

Duchenne muscular dystrophy is an X-linked recessive muscle wasting disease caused by the absence of the muscle cytoskeletal protein, dystrophin. Dystrophin is a member of the spectrin superfamily of proteins and is closely related in sequence similarity and functional motifs to three proteins that constitute the dystrophin related protein family, including the autosomal homologue, utrophin. An alternative strategy circumventing many problems associated with somatic gene therapies for Duchenne muscular dystrophy has arisen from the demonstration that utrophin can functionally substitute for dystrophin and its over-expression in muscles of dystrophin-null transgenic mice completely prevents the phenotype arising from dystrophin deficiency. One potential approach to increase utrophin levels in muscle for possible therapeutic purpose in humans is to increase expression of the utrophin gene at a transcriptional level via promoter activation. This has lead to an interest in the identification and manipulation of important regulatory regions and/or molecules that increase the expression of utrophin and their delivery to dystrophin-deficient tissue. As pre-existing cellular mechanisms are utilized, this approach would avoid many problems associated with conventional gene therapies.
 ...
PMID:The role of utrophin in the potential therapy of Duchenne muscular dystrophy. 1220 1

Duchenne muscular dystrophy is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene. Delivery of functionally effective levels of dystrophin to immunocompetent, adult mdx (dystrophin-deficient) mice has been challenging because of the size of the gene, immune responses against viral vectors, and inefficient infection of mature muscle. Here we show that high titer stocks of three different gutted adenoviral vectors carrying full-length, muscle-specific, dystrophin expression cassettes are able to efficiently transduce muscles of 1-yr-old mdx mice. Single i.m. injections of viral vector restored dystrophin production to 25-30% of mouse limb muscle 1 mo after injection. Furthermore, functional tests of virally transduced muscles revealed almost 40% correction of their high susceptibility to contraction-induced injury. Our results show that functional abnormalities of dystrophic muscle can be corrected by delivery of full-length dystrophin to adult, immunocompetent mdx mice, raising the prospects for gene therapy of muscular dystrophies.
 ...
PMID:Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin. 1227 Nov 28

Mdx mouse, the animal model of Duchenne muscular dystrophy, develops an X-linked recessive inflammatory myopathy with an apparent sustained capacity for muscle regeneration. We analysed whether changes in the skeletal muscle during myonecrosis and regeneration would correlate with functional alterations in peripheral lymphoid tissues. Here we show that during the height of myonecrosis, mdx mice display marked atrophy of peripheral lymph nodes and extensive muscle inflammation. In contrast, enlargement of draining lymph nodes with accumulation of CD4+ CD44+, CD4+ CD25+, CD8+ CD44+ T lymphocytes and type-2 B cells was consistently observed during amelioration of the muscle lesion. In addition, regeneration of the muscular tissue was accompanied by concomitant increase of immunoglobulin-secreting cells in regional lymph nodes and bone marrow. Double immunolabelling analysis revealed intense B cell proliferation and formation of germinal centre in the follicles of dystrophic regional lymph nodes. Furthermore, lymph node cells produced large amounts of IFN-gamma but not IL-4, IL-6 or IL-10 after in vitro mitogen stimulation with Concanavalin A. As these alterations occurred mainly during the recovery period, we suggested that local activation of the immune system could be an influence which mitigates the myonecrosis of muscular tissue in the mdx dystrophic mouse.
 ...
PMID:Resolution of skeletal muscle inflammation in mdx dystrophic mouse is accompanied by increased immunoglobulin and interferon-gamma production. 1238 91

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by a lack of dystrophin. To eliminate the need for immunosuppressive drugs, transplantation of genetically modified autologous myoblasts has been proposed as a possible therapy for this myopathy. An HSV-1 amplicon vector (HSVDGN), containing a 17.3-kb full-length MCK-driven mouse dystrophin cDNA, an eGFP gene, and a neomycin resistance gene driven by CMV or SV40 promoters, respectively, was constructed and used to transduce mdx primary myoblasts. The presence of the eGFP and neomycin resistance genes facilitated the evaluation of the initial transduction efficiency and the permanent transduction frequency. At low multiplicities of infection (MOI 1-5), the majority of myoblasts (60-90%) expressed GFP. The GFP-positive mdx myoblasts were sorted by FACS and selected with neomycin (300 microg/ml) for 2 weeks. Up to 2% of initially infected mdx myoblasts stably expressed the three transgenes without further selection at that time. These altered cells were grafted into the tibialis anterior muscles of 18 mdx mice. Some of the mice were immunosuppressed with FK506 due to the anticipation that eGFP and the product of neomycin resistance gene might be immunogenic. One month after transplantation, numerous muscle fibers expressing mouse dystrophin were detected by immunohistochemistry, in both immunosuppressed (10-50%) and nonimmunosuppressed (5-25%) mdx mice. Our results demonstrated the capability of permanently expressing a full-length dystrophin in dystrophic myoblasts with HSV-1 amplicon vector and raised the possibility of an eventual treatment of DMD based on the transplantation of genetically modified autologous myoblasts.
 ...
PMID:Autotransplantation in mdx mice of mdx myoblasts genetically corrected by an HSV-1 amplicon vector. 1258 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>