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)

X-linked inherited hearing impairment is a group of heterogeneous disorders accounting for less than 2% of hereditary hearing loss. DFN4, a sex-linked hearing impairment associated with profound sensorineural hearing loss, has been previously mapped to Xp21.2, a region containing the DMD locus. We have identified a family from Turkey with deafness in which the disease maps to and refines the DFN4 locus. In contrast to the previous family, the crossover points are entirely within the DMD locus. Two-point lod score analysis for the markers DXS 997, DXS 1214, and DXS 1219 showed a lod score of 2. 59. 5' and 3' crossovers were between DMD 44 and DXS 1219 and between DXS 1214 and DXS 985, respectively, suggesting that DFN4 is either an allele of DMD or a mutation in a DMD nested gene. The restriction of the DFN4 locus to DMD suggests that dystrophin may play an important role in hearing.
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PMID:A second family with nonsyndromic sensorineural hearing loss linked to Xp21.2: refinement of the DFN4 locus within DMD. 979 5

Linkage analysis was performed in three generations of a French family segregating a syndromal form of X-linked mental retardation. All affected males had neonatal hypotonia, seizures, muscular hypodevelopment, and severe mental deficiency. A peak lod score of 2.90 at a recombination fraction of theta = 0 was detected for DXS 1052 and DXS 451 (Xp22.13). Recombination between the disease locus and the polymorphic markers in DXS7163 and DXS1238 suggested a gene mapping to the Xp22.13-Xp21.2 region. Three candidate genes in this region were investigated: the cDNA for kinase Rsk-2 involved in Coffin-Lowry syndrome, the brain-specific exon of a transcript in the DMD locus (DP140 isoform of dystrophin), and exon 18 of the glycerol kinase gene, which is specific to fetal brain transcripts. All three sequences were normal.
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PMID:Evidence for a new X-linked mental retardation gene in Xp21-Xp22: clinical and molecular data in one family. 1049

Left ventricular thrombosis and systemic emboli have been demonstrated to complicate cardiomyopathy in Duchenne and Becker muscular dystrophy (DMD, BMD). We investigated plasma levels of prothrombin fragment 1+2 (F1+2). thrombin-antithrombin III complex (TAT) and circulating levels of tumor necrosis factor-alpha (TNF-alpha), a procoagulant cytokine that has been shown to be elevated in patients with depressed cardiac function, in 20 patients with DMD and 12 patients with BMD as compared with 30 age-matched control subjects. Significantly elevated levels of F1+2 (DMD: 1.4+/-0.8 nmol/l; BMD: 1.8+/-0.8 nmol/l vs. controls: 0.7+/-0.2 nmol/l, p <0.01 and p <0.001, respectively), TAT complexes (DMD: 4.7+/-2.7 microg/l, BMD: 5+/-2.3 microg/l vs. controls: 1.6+/-0.5 microg/l, p <0.001) and TNF-alpha (54+/-9 vs. 25+/-7 pg/ml, p <0.001) were observed in patients with the dystrophic disease compared to control subjects. A significantly negative correlation was also found between F1+2 and TAT complexes and left ventricular ejection fraction (r = -0.65, p <0.0001; r = -0.80, p < 0.0001, respectively) and a positive correlation between F1+2 and TAT complexes and serum TNF-alpha levels (r = 0.67, p <0.0001; r = 0.70, p <0.0001, respectively). Our results indicate a hypercoagulable state in X-linked dystrophic patients. A possible relationship between haemostatic activation, left ventricular dysfunction and TNF-alpha system upregulation may be suggested.
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PMID:Haemostatic abnormalities, cardiac involvement and serum tumor necrosis factor levels in X-linked dystrophic patients. 1023 36

Duchenne (DMD) and Becker (BMD) are allelic forms of a X-linked neuromuscular disorder. Both are caused by mutations arising in the gene encoding dystrophin, a cytoskeletal protein. Two-thirds of DMD/BMD patients have large deletions localised in two hot spots, and the remaining cases are presumed to be caused by point mutations. Since Duchenne muscular dystrophy is a serious disorder for which at present there is no effective treatment, much emphasis has been given to prevention. This involves the ascertainment of women likely to have an affected son, and the provision of genetic counselling and prenatal diagnosis for such women. Accurate carrier detection and genetic counselling depend upon identifying the mutation itself in the proband. Large deletions are easily identified using multiplex polymerase chain reaction (PCR) whereas detection of point mutations is restricted to a few number of specialized laboratories. Hence carrier and prenatal diagnosis in 40% of families rely heavily on indirect approaches which presents major drawbacks and are not applicable in sporadic cases of DMD or BMD. We developped a strategy for searching small alterations in the dystrophin gene. As most of the non-deletion mutations cause a premature termination of translation, we have used the Protein Truncation Test to scan specifically the dystrophin transcripts isolated from muscle biopsies. This approach allowed to detect the disease-causing mutations in more than 90% of the patients who have been investigated; his efficiency is thus significantly higher than DNA-based strategies. The identification of the mutation in non deleted sporadic cases allows the at-risks females to benefit from an accurate diagnosis. Also, the characterization of the molecular defects provides a better understanding of the molecular pathology of the dystrophin gene.
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PMID:[Genotypic diagnosis of Duchenne and Becker muscular dystrophies]. 1043 64

The large size of many disease genes and the multiplicity of mutations complicate the design of an adequate assay for the identification of disease-causing variants. One of the most successful methods for mutation detection is the single strand conformation polymorphism (SSCP) technique. By varying temperature, gel composition, ionic strength and additives, we optimised the sensitivity of SSCP for all 27 exons of the CFTR gene. Using simultaneously SSCP and heteroduplex (HD) analysis, a total of 80 known CF mutations (28 missense, 22 frameshift, 17 nonsense, 13 splicesite) and 20 polymorphisms was analysed resulting in a detection rate of 97.5% including the 24 most common mutations worldwide. The ability of this technique to detect mutations independent of their nature, frequency, and population specificity was confirmed by the identification of five novel mutations (420del9, 1199delG, R560S, A613T, T1299I) in Swiss CF patients, as well as by the detection of 41 different mutations in 198 patients experimentally analysed. We present a three-stage screening strategy allowing analysis of seven exons within 5 hours and analysis of the entire coding region within 1 week, including sequence analysis of the variants. Additionally, our protocol represents a general model for point mutation analysis in other genetic disorders and has already been successfully established for OTC deficiency, collagene deficiency, X-linked myotubular myopathy (XLMTM), Duchenne and Becker muscular dystrophy (DMD, BMD), Wilson disease (WD), Neurofibromatosis I and II, Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsies, and defects in mitochondrial DNA. No other protocol published so far presents standard SSCP/HD conditions for mutation screening in different disease genes.
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PMID:Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. 1043 67

Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscular dystrophies. The isolation of the defective gene in DMD/BMD has led to a better understanding of the disease process and has promoted studies regarding the application of molecular therapy. The purpose of this review is to present the progress made in this area of research with particular reference to dystrophin Kobe. Based on the results from the molecular analysis of dystrophin Kobe, we propose a novel molecular therapeutic method for DMD in which antisense oligonucleotides transform DMD into a milder phenotype by inducing exon skipping. In addition, current proposals for the molecular therapy of DMD are discussed.
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PMID:Duchenne and Becker muscular dystrophy: from gene diagnosis to molecular therapy. 1210 70

Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked diseases resulting from a defect in the dystrophin gene located on Xp21. DMD is the most frequent neuromuscular disease in humans (1/3500 male newborn). Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. We have analyzed DNA from 72 Moroccan patients with DMD/BMD using the multiplex polymerase chain reaction (PCR) to screen for exon deletions within the dystrophin gene, and to estimate the frequency of these abnormalities. We found dystrophin gene deletions in 37 cases. Therefore the frequency in Moroccan DMD/BMD patients is about 51.3%. All deletions were clustered in the two known hot-spots regions, and in 81% of cases deletions were detected in the region from exon 43 to exon 52. These findings are comparable to those reported in other studies. It is important to note that in our population, we can first search for deletions of DMD gene in the most frequently deleted exons determined by this study. This may facilitate the molecular diagnosis of DMD and BMD in our country.
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PMID:Analysis of Dystrophin Gene Deletions by Multiplex PCR in Moroccan Patients. 1248 81

IL1RAPL1 (interleukin-1 receptor accessory protein-like, gene 1) has recently been shown to be mutated in patients with X-linked mental retardation. Clinical experience has suggested that patients with the contiguous gene syndrome, complex glycerol kinase deficiency (cGKD), will have mental retardation (MR) if they have deletions extending from the GK gene into the DMD gene and/or involving a significant extension telomeric from DAX1. We examined cell lines from patients with cGKD whose clinical features would be informative and would allow us to determine if IL1RAPL1 deletions can help to explain the MR in patients with deletions extending telomeric from DAX1. Our results showed that nearly all patients with deletions involving DAX1, but not DMD, had MR if IL1RAPL1 was deleted. If ILIRAPLI and DMD were intact, the patients with DAX1 deletions only rarely had normal development. Deletions in DNA from patients with cGKD who exhibited MR and had normal IL1RAPL1 all involved the GK and DMD genes. Our data are consistent with the association of IL1RAPL1 gene deletion and MR in the majority of patients with cGKD and deletions extending telomeric from DAX1.
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PMID:IL1RAPL1 is associated with mental retardation in patients with complex glycerol kinase deficiency who have deletions extending telomeric of DAX1. 1530 Aug 57

Common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. They are biologically significant due to their role in a number of genomic alterations that are frequently found in many different types of cancer. The first CFS to be cloned and characterized was FRA3B, the most active CFS in the human genome. Instability within this region extends for over 4.0 Mbs and contained within the center of this CFS is the FHIT gene spanning 1.5 Mbs of genomic sequence. There are frequent deletions and other alterations within this gene in multiple tumor types and the protein encoded by this gene has been demonstrated to function as a tumor suppressor in vitro and in vivo. In spite of this, FHIT is not a traditional mutational target in cancer and many tumors have large intronic deletions without any exonic alterations. There are several other very large genes found within CFS regions including Parkin (1.37 Mbs in FRA6E), GRID2 (1.47 Mbs within 4q22.3), and WWOX (1.11 Mbs within FRA16D). These genes also appear to function as tumor suppressors but are not traditional mutational targets in cancer. Each of these genes is highly conserved and the regions spanning them are CFSs in mice. We have now examined lists of the largest human genes and found forty that span over one megabase. Many of these are derived from chromosomal bands containing CFSs. BACs within these genes are being utilized as FISH probes to determine if these are also CFS genes. Thus far we have identified the following as CFS genes: CNTNAP2 (2.3 Mbs in FRA7I), DMD (2.09 Mbs in FRAXC), LRP1B (1.9 Mbs in FRA2F), CTNNA3 (1.78 Mbs in FRA10D), DAB1 (1.55 Mbs in FRA1B), and IL1RAPL1 (1.36 Mbs in FRAXC). Although, these genes are also not traditional mutational targets in cancer they do exhibit loss of expression in multiple tumor types suggesting that they may also function as tumor suppressors. Many of the large CFS genes are involved in neurological development. Parkin is mutated in autosomal recessive juvenile Parkinsonism and deletions in mice are associated with the mouse mutant Quaking (viable). Spontaneous mouse mutants in GRID2 and DAB1 are associated with Lurcher and Reelin, respectively. In humans, alterations in IL1RAPL1 cause X-linked mental retardation and loss of WWOX is associated with Tau phosphorylation. We propose that the instability-induced alterations in these genes contribute to cancer development in a two-step process. Initial alterations will primarily occur within intronic regions, as these genes are greater than 99% intronic. These are not benign. Instead, they alter the repertoire of transcripts produced from these genes. As cancer progresses deletions will begin to encompass exons resulting in gene inactivation. These two types of alterations occurring in multiple large CFS genes may contribute significantly to the heterogeneity observed in cancer. There are also important potential linkages between normal neurological development and the development of cancer mediated by alterations in these genes.
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PMID:Common fragile sites, extremely large genes, neural development and cancer. 1622 25

Genetic testing of Duchenne and Becker muscular dystrophies (DMD/BMD) is a difficult task due to the occurrence of deletions or duplications within dystrophin (DMD) gene that requires dose sensitive tests. We developed three multiplex quantitative real-time PCR assays for dystrophin exon 5, 45, and 51 within two major hotspots of deletion/duplication. Each exon was co-amplified with a reference X-linked gene and the copy number of the target fragment was calculated by comparative threshold cycle method (delta deltaC(t)). We compared the performance of this method with previously described end-point PCR fluorescent analysis (EPFA) by studying 24 subjects carrying DMD deletions or duplications. We showed that Q-PCR is an accurate and sensitive technique for the identification of deletions and duplications in DMD/BMD. Q-PCR is a valuable tool for independent confirmation of EPFA screening, particularly when deletions/duplications of single exons occur or for rapid identification of known mutations in at risk carriers.
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PMID:Multiplex real-time PCR for detection of deletions and duplications in dystrophin gene. 1629 82


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