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)

Dystonia and parkinsonism are two major representatives of movement disorders. The X-linked dystonia-parkinsonism syndrome (XDP) serves as a model system for the study of both dystonia and parkinsonism since both symptom complexes occur together and are inherited as Mendelian traits with very high penetrance. XDP, which is endemic to the Philippine island of Panay, originated by a single mutation ("genetic founder effect"), thus assuring homogeneity of the disorder at the molecular level. The disease locus, DYT3, has been assigned to the proximal long arm (Xq12-21.1) of the human X chromosome. A strategy is described to isolate this gene by positional cloning. The rationale of this strategy, the major methods involved and technical terms are explained.
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PMID:The X-linked dystonia-parkinsonism syndrome (XDP): clinical and molecular genetic analysis. 136 36

The study of rare genetic forms of dystonia and parkinsonism permits positional cloning of genes potentially involved in more common, multifactorial forms of these diseases. One movement disorder amenable to molecular genetic analysis is the X-linked dystonia-parkinsonism syndrome (XDP). This disease is endemic to the Philippines where it originated by a genetic founder effect. Linkage analysis was performed with DNA from 14 XDP kindreds by using 12 polymorphic DNA sequences in Xp11-Xq22. Two-point analysis demonstrated maximum lod scores of 5.45, 4.95, 4.28, and 5.99 for DXS106, DXS159, PGK1, and DXS72, respectively, at recombination fractions of zero (DXS106 and DXS159), .01 (PGK1), and .04 (DXS72). Multipoint analysis resulted in a maximum-likelihood score (Zmax) of 8.41 with a (Zmax - 1) support interval of 9 cM between DXS159 and DXS72 (Xq12-q21.1). In 19 XDP kindreds significant linkage disequilibrium was found for loci DXS72 (delta = .47), PGK1 (delta = .36), DXS95 (delta = .30), DXS106 (delta = .28), and DXS159 (delta = .26). These data indicate that the gene mutated in XDP (locus DYT3) is located in Xq12-q21.1.
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PMID:Dystonia-parkinsonism syndrome (XDP) locus: flanking markers in Xq12-q21.1. 155 Jan 25

A YAC contig was constructed of Xq13.1 in order to sublocalize the X-linked dystonia-parkinsonism (XDP) syndrome locus, DYT3. The contig spans a region of approximately 1.8 Mb and includes loci DXS453/DXS348/IL2R gamma/GJB1/CCG1/DXS559. For the construction of the contig, nine sequence-tagged sites and four short tandem repeat polymorphisms (STRPs) were isolated. The STRPs, designated as 4704#6 (DXS7113), 4704#7 (DXS7114), 67601 (DXS7117), and B4Pst (DXS7119) were assigned to a region flanked by DXS348 proximally and by DXS559 distally. Their order was DXS348/4704 #6/4704 #7/67601/B4Pst/DXS559. They were applied to the analysis of allelic association and of haplotypes in 47 not-obviously-related XDP patients and in 105 Filipino male controls. The same haplotype was found at loci 67601 (DXS7117) and B4Pst (DXS7119) in 42 of 47 patients. This percentage of common haplotypes decreased at the adjacent loci. The findings, together with the previous demonstration of DXS559 being the distal flanking marker of DYT3, assign the disease locus to a small region in Xq13.1 defined by loci 67601 (DXS7117) and B4Pst (DXS7119). The location of DYT3 was born out by the application of a newly developed likelihood method for the analysis of linkage disequilibrium.
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PMID:Assignment of the dystonia-parkinsonism syndrome locus, DYT3, to a small region within a 1.8-Mb YAC contig of Xq13.1. 766 93

The locus (DYT3) underlying the X-linked dystonia-parkinsonism syndrome (XDP) was delineated within proximal Xq12-Xq13.1 by analysis of linkage, allelic association, and haplotypes. Short tandem repeat polymorphisms at loci DXS227, DXS559, DXS453, DXS106, DXS339, and DXS135 were studied. The occurrence of a recombination within a three-generation family established DXS559 as the distal flanking marker of DYT3. /phi/ and /delta/ values were determined as indicators of the degree of allelic association between DYT3 and the six marker loci. In addition, haplotype analysis was performed at the loci studied. The findings establish DXS106 as the proximal flanking marker of DYT3. Given an approximate distance between DXS106 and DXS559 of 3.0 Mb, isolation of DYT3 is now feasible by positional cloning techniques.
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PMID:DXS106 and DXS559 flank the X-linked dystonia-parkinsonism syndrome locus (DYT3). 782 58

We have mapped AFX1 and p54nrb to a yeast artificial chromosome (YAC) contig of Xq13.1 that harbors the X-linked dystonia parkinsonism (XDP) locus DYT3. AFX1 is flanked by loci DXS7116 and Il2R gamma, and p54nrb by loci DXS6673E and DXS7120. The exon-intron structure of both genes was analyzed. AFX1 is composed of three exons with most of exon 3 being untraslated. p54nrb is made up of 12 exons ranging in size from 40 bp to 1227 bp. The start codon is in exon 3 and the stop codon in exon 12. Both genes are expressed in the brain, among other tissues. AFX1 and p54nrb were excluded as candidates of DYT3 by sequencing of the exons and the flanking intronic sequences in an XDP patient and a control, and by Northern blot analysis.
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PMID:AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism. 934 72

X-linked dystonia-parkinsonism (XDP) is a recessive disorder characterized by generalized dystonia with some patients exhibiting parkinsonism. The disease gene, DYT3, is located between DXS453 (DXS993) and DXS559, and strongest linkage disequilibrium is found distal to DXS7117 and proximal to DXS559. We have isolated and analyzed four novel polymorphic markers between DXS7117 and DXS559 and, by haplotype analysis, have narrowed the candidate interval to <350 kb. A sequence-ready contig of 700 kb has been constructed spanning DXS7117 to DXS559 and is composed of 35 PACs, BACs, and cosmids. Nine genes and novel ESTs have been mapped into this contig, and mutations in the coding regions and intron-exon borders of two genes have been excluded as the cause of XDP. Several of the other genes and ESTs located within the contig code for proteins implicated in normal brain development and function and are candidates for DYT3.
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PMID:Refined linkage disequilibrium and physical mapping of the gene locus for X-linked dystonia-parkinsonism (DYT3). 1049 31

To date, at least 12 types of primary dystonia can be distinguished on a genetic basis. A 3-bp deletion in the DYT1 gene causes early onset, generalized torsion dystonia (TD), and mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes result in dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor in one large family (DYT11) has recently been implicated in myoclonus-dystonia. Furthermore, seven other loci for dystonia genes have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), three types of paroxysmal dystonia (DYT8-10), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia-parkinsonism (DYT12). No positive linkage results have yet been obtained for autosomal recessive TD (DYT2) and several other families of different types of dominantly inherited TD (DYT4). In addition, hereditary secondary dystonia may occur as part of familial diseases of the basal ganglia, metabolic and storage disorders, and various X-linked and other familial neurodegenerative syndromes affecting the basal ganglia. It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.
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PMID:[Genetics of dystonia]. 1091 37

We searched for novel genes as candidates of X-linked dystonia parkinsonism (XDP) in the critical interval of Xq13.1 that harbors the disease locus (DYT3). A gene, ACRC (acidic repeat containing), was discovered by a combination of in silico and "wet" experiments. ACRC is composed of at least 12 exons and 11 introns. It is expressed in all tissues tested, including skeletal muscle, liver, kidney, pancreas, heart, lung, and brain. Highest levels of expression are found in skeletal muscle. The ACRC protein is characterized by a previously undescribed acidic repeat tract of 21 units of 8-10 amino acids. The N-terminal portion of the protein is highly acidic (pI=3.2), and the C-terminal region is basic (pI=10.2). There are nuclear localization signals in its C-terminal portion. Extensive mutation analysis of the transcribed region of the gene, including intron-exon boundaries and the 5' and 3' untranslated intervals, did not reveal a mutation in XDP patients. Exclusion of a mutation in the transcribed portion of this and all other known genes within the DYT3 critical interval suggests that XDP is most likely caused by a mutation in a regulatory region of a gene within the critical interval, or by a structural rearrangement.
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PMID:ACRC codes for a novel nuclear protein with unusual acidic repeat tract and maps to DYT3 (dystonia parkinsonism) critical interval in xq13.1. 1171 1

Currently, at least 12 types of dystonia can be distinguished on a genetic basis. Advances in the molecular genetics of dystonia have led to the recent identification of a 3-bp deletion in the DYT1 gene, causing early-onset generalized torsion dystonia (TD), and to the detection of mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes causing dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor has been shown to be associated with myoclonus-dystonia in one family. In addition, six other dystonia gene loci have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), two types of paroxysmal dystonia (DYT8, DYT9), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia parkinsonism (DYT12). No positive linkage studies have as yet been reported for autosomal recessive TD (DYT2) and in several other large families with various types of dominantly inherited TD (DYT4). It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.
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PMID:Genetics of primary dystonia. 1219 83

X-linked dystonia parkinsonism (XDP) is an X-linked recessive adult onset movement disorder characterized by both dystonia and parkinsonism. We report delineation of the disease gene within a 300-kb interval of Xq13.1 by allelic association. Sequencing of this region in a patient revealed five disease-specific single-nucleotide changes (here referred to as DSC) and a 48-bp deletion unique to XDP. One of the DSCs is located within an exon of a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of three different transcription start sites that encode four different transcripts. Two of these transcripts include distal portions of the TAF1 gene (TATA-box binding protein-associated factor 1) and are alternatively spliced. Three exons overlap with ING2 (a putative tumor suppressor) and with a homologue of CIS4 (cytokine-inducible SH2 protein 4), both of which are encoded by the opposite strand. Although all DSCs are located within this multiple transcript system, only DSC3 lies within an exon. This exon is used by all alternative transcripts making a pathogenic role of DSC3 in XDP likely. The multiple transcript system is therefore referred to as DYT3 (disease locus in XDP).
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PMID:Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. 1292 96


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