Alternative titles; symbols
SNOMEDCT: 698279003; ORPHA: 53351; DO: 0090057;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq13.1 | Dystonia-Parkinsonism, X-linked | 314250 | X-linked recessive | 3 | TAF1 | 313650 |
A number sign (#) is used with this entry because X-linked dystonia-parkinsonism (XDP) is caused by an SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion in an intron of the TATA-binding protein-associated factor-1 gene (TAF1; 313650) on chromosome Xq13.
XDP is a homogeneous disorder introduced by a founder effect in the Filipino population. In the local Filipino dialect, XDP is referred to as 'lubag,' meaning 'twisted' (Nolte et al., 2003; Evidente et al., 2004).
Lee et al. (1976) identified an unusually high frequency of torsion dystonia in Panay, the sixth largest of the islands of the Philippines. Of 28 Filipino cases, 23 came from that island and 19 from the province of Capiz. All cases were in males. Six sets of affected brothers and 2 families with 2-generation involvement consistent with X-linked recessive inheritance were observed. The mean age of onset was 31 years. Spasmodic eye blinking was the first symptom in 4 patients. Kupke et al. (1990) conducted a more extensive investigation in Panay. Twenty-one pedigrees were documented in which several members were affected. Among 120 sons of carrier mothers, 64 (52%) were affected. One affected female was reported. The average age of onset was 38.6 years (range, 12-56 years), which is similar to that in the adult-onset autosomal dominant form. However, the X-linked form tended to generalize in most patients within 7 years of onset. Frequently, parkinsonian symptoms may accompany or precede dystonia in these patients (Fahn and Moskowitz, 1988). It subsequently became certain that the X-linked parkinsonism reported by Johnston and McKusick (1963) in a Filipino kindred, previously cataloged as a distinct entity, was in fact the X-linked torsion dystonia-parkinsonism syndrome. The proband in the study of Johnston and McKusick (1963) belonged to the family that had been studied by Fahn and Moskowitz (1988). Wilhelmsen et al. (1991) referred to this disorder by the name 'lubag,' a term used by the families when intermittent twisting movements were present. The families also used the term 'wa-eg' when sustained twisting postures occurred, and 'sud-sud,' an onomatopoeic term derived from the sound of sandals slapping the pavement.
Muller et al. (1990) studied the natural history of the disorder in 42 affected individuals from 21 Filipino families. The mean age of onset was 34.8 +/- 8.1 (S.D.) years. First manifestations were noted in the head and neck in 39%, in the lower limbs in 33%, in the upper limbs in 24%, and in the trunk in 9%. At least one 'parkinsonian symptom' (bradykinesia, rigidity, loss of postural reflexes, and 'fine' resting tremor) was found in 36% of the cases. Within families, some affected males had parkinsonian symptoms but others did not.
See 304700 for discussion of the dystonia-deafness syndrome.
Evidente et al. (2004) found that 9 (53%) of 17 women from 5 unrelated XDP families who carried the DSC3 change or the XDP haplotype were symptomatic or had abnormal neurologic examinations. Of 8 symptomatic women, 7 were heterozygous and 1 was homozygous for the DSC3 change. Average age at onset for the women was 52 years (range, 26 to 75 years), with onset of parkinsonism or tremor in 4 patients, chorea in 3, and dystonia in 1. The features were generally mild, with only 1 woman treated with levodopa. Evidente et al. (2004) suggested that extreme X-inactivation likely underlies the disease in a subset of women carriers.
Nolte et al. (2003) considered several possibilities for the pathogenesis of XDP. The presence of INGX (300452) and of the CIS4 homolog on the opposite strand of DYT3 might indicate regulation of these 2 genes by at least some transcripts of DYT3. Transcript 3 covers portions of INGX and therefore could be involved in its regulation by antisense RNA, and all 4 transcripts partially overlap with the CIS4 homolog. Given that all 4 transcripts include DSC3 containing exon 4, potentially all transcripts could cause XDP by interfering with the function of the CIS4 homolog, provided it is not a pseudogene. An example of potential antisense regulation by disease gene is SCA8 (603680), the gene implicated in spinocerebellar ataxia-8 (608768). In that case, portions of the SCA8 gene might be a natural antisense RNA, because the SCA8 chain partially overlaps with the Kelch-like 1 (KLHL1; 605332) gene that is encoded by the opposite strand. Yet another possibility of the molecular pathologic mechanism of DSC3 action is a missense mutation in variant 4. This transcript potentially encodes a small polypeptide of 51 amino acids, and the base change would result in an exchange of an arginine for a cysteine.
Goto et al. (2005) performed postmortem examination of the basal ganglia in 7 male patients with XDP, of whom 5 manifested dystonia and 2 had advanced stage parkinsonism. Immunostaining for the neurochemical marker calcineurin (114105) and the matrix marker calbindin (114050) showed that the 5 patients with dystonia had patchy areas of preserved neurons in the striosome and relative sparing of the matrix compartment, whereas the parkinsonian patients had severe depletion of the striosomal pathway with involvement of the matrix-based pathway as well. Goto et al. (2005) postulated that in earlier stages of XDP, severe loss of striosomal GABAergic projection neurons may lead to disinhibition of nigral dopaminergic neurons, resulting in a hyperkinetic dystonia disorder. At the later stage, when parkinsonism predominates, there may be greater involvement of the matrix compartment, leading to reduction of matrix-based projections and resulting in an 'extranigral form' of parkinsonism.
Kupke et al. (1990) mapped the gene for X-linked torsion dystonia to Xq21 by linkage to DNA and other markers in that region. They found a maximum lod score of 3.06 at theta = 0.0 for linkage with DXYS2, which maps to Xq21.3. Kupke et al. (1992) determined by linkage analysis that the DYT3 locus lies in a 9-cM interval between DXS159 and DXS72 (Xq12-q21.1). In 19 kindreds, significant linkage disequilibrium was found with PGK1 (311800) and 4 DNA markers located in the region Xq12-q21.1. Using 4 dinucleotide tandem repeat (DNTR) sequences from Xq13-derived YACs, Graeber et al. (1992) narrowed the localization of DYT3 to a region in Xq13 and identified flanking markers. The assignment to this region was further supported by highly significant allelic association between DYT3 and the 4 DNTR loci located in a region defined by PGK1 and DXS56. Muller et al. (1994) concluded that the DYT3 locus is within Xq12-q13.1, flanked by DXS106 proximally and DXS559 distally. The distance between these 2 markers was estimated to be approximately 3.0 Mb. Haberhausen et al. (1995) narrowed the DYT3 locus to a smaller region defined by DXS7117 and DXS7119 within a 1.8-Mb YAC contig. The location was supported by application of a newly developed likelihood method for the analysis of linkage disequilibrium.
Through association studies with short tandem repeat polymorphisms (STRPs) from the critical linkage region, Nemeth et al. (1999) facilitated assignment of DYT3 to an interval of approximately 400 kb. Extensive sequence analyses of both coding and noncoding regions of these genes in patients with X-linked dystonia-parkinsonism did not reveal a mutation, suggesting that XDP is caused by either a small structural rearrangement, a mutation in a regulatory element of a known gene, or a mutation in a hitherto unknown gene.
Nolte et al. (2001) excluded the transcribed portion of the ACRC gene (300369) as the site of mutation in X-linked dystonia-parkinsonism. They noted that the transcribed portion of several other genes had been excluded and suggested that XDP is most likely caused by mutation in a regulatory region of a gene within the critical interval or by a structural rearrangement.
Nolte et al. (2003) sequenced 260 kb of the critical interval in an XDP patient. Comparison to the published sequence of the interval revealed 2 SNPs that were polymorphic in patients only, 2 SNPs that were also polymorphic in controls, and 5 disease-specific single-nucleotide changes (DSC1, 2, 3, 10, and 12). The detection of only 4 SNPs within the 260 kb of the X chromosome sequence indicated that this region of the genome is of unusually low heterozygosity. The disease-specific changes were found in all XDP patients (N = 46) but in none of 178 unaffected male and female Filipino controls (208 X chromosomes) without a family history of XDP. In addition to the XDP-specific single-nucleotide changes, a 48-bp deletion was detected exclusively in patients. Only 1 disease-specific single-nucleotide change, referred to as DSC3, was located in a region of unique DNA not related to an annotated gene. DSC3 is a C-to-T transition at base 797 in exon 4 of a GenBank sequence (AJ549245.1). Extensive RT-PCR analysis of RNA isolated from patient and control lymphoblastoid cells and from human cordate nucleus by using primers from sequences surrounding DSC3 identified a transcribed fragment of 782 bp that is encoded by 2 exons separated by an intron of 987 bp. DSC3 is located in one of these exons. The novel transcript was given the gene name DYT3 in accordance with the Hugo nomenclature recommendation. The exon carrying DSC3 was found to be located in a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of 3 different transcription start sites that encode 4 different transcripts. Two of these transcripts include distal portions of the TAF1 gene and are alternatively spliced. Three exons overlap with INGX and with a homolog of CIS4 (605118), both of which are encoded by the opposite strand. The exon containing DSC3 is used by all alternative transcripts, making a pathogenic role of DSC3 in XDP likely.
In a search for the causative gene responsible for X-linked dystonia-parkinsonism, Makino et al. (2007) performed genomic sequencing analysis of the critical mapping region of the DYT3 locus on Xq13.1, followed by expression analysis of brain tissues from XDP individuals. They found a disease-specific SVA retrotransposon insertion in intron 32 of the TAF1 gene (313650.0001), which encodes the largest component of the TFIID complex. Studies of XDP postmortem brain showed significantly decreased expression levels of TAF1 and of the dopamine receptor D2 gene (DRD2; 126450). Makino et al. (2007) also identified an abnormal pattern of DNA methylation in the retrotransposon in the genome from the patient's caudate, which could account for decreased expression of TAF1. The findings suggested that reduced expression of 1 or more neuron-specific isoforms of TAF1 is responsible for XDP.
Evidente, V. G. H., Nolte, D., Niemann, S., Advincula, J., Mayo, M. C., Natividad, F. F., Muller, U. Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ('Lubag') in women. Arch. Neurol. 61: 1956-1959, 2004. [PubMed: 15596620] [Full Text: https://doi.org/10.1001/archneur.61.12.1956]
Fahn, S., Moskowitz, C. X-linked recessive dystonia and parkinsonism in Filipino males. (Abstract) Ann. Neurol. 24: 179 only, 1988.
Goto, S., Lee, L. V., Munoz, E. L., Tooyama, I., Tamiya, G., Makino, S., Ando, S., Dantes, M. B., Yamada, K., Matsumoto, S., Shimazu, H., Kuratsu, J., Hirano, A., Kaji, R. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann. Neurol. 58: 7-17, 2005. [PubMed: 15912496] [Full Text: https://doi.org/10.1002/ana.20513]
Graeber, M. B., Kupke, K. G., Muller, U. Delineation of the dystonia-parkinsonism syndrome locus in Xq13. Proc. Nat. Acad. Sci. 89: 8245-8248, 1992. [PubMed: 1518853] [Full Text: https://doi.org/10.1073/pnas.89.17.8245]
Haberhausen, G., Schmitt, I., Kohler, A., Peters, U., Rider, S., Chelly, J., Terwilliger, J. D., Monaco, A. P., Muller, U. Assignment of the dystonia-Parkinsonism syndrome locus, DYT3, to a small region within a 1.8-Mb YAC contig of Xq13.1. Am. J. Hum. Genet. 57: 644-650, 1995. [PubMed: 7668293]
Johnston, A. W., McKusick, V. A. Sex-linked recessive inheritance in spastic paraplegia and parkinsonism. In: Gedda, L. (ed.): Proceedings of the Second International Congress on Human Genetics, Rome, Sept. 6-12, 1961. Vol. 3. Rome: Instituto G. Mendel (pub.) 1963. Pp. 1652-1654.
Kupke, K. G., Graeber, M. B., Muller, U. Dystonia-parkinsonism syndrome (XDP) locus: flanking markers in Xq12-q21.1. Am. J. Hum. Genet. 50: 808-815, 1992. [PubMed: 1550125]
Kupke, K. G., Lee, L. V., Muller, U. Assignment of the X-linked torsion dystonia gene to Xq21 by linkage analysis. Neurology 40: 1438-1442, 1990. [PubMed: 1975433] [Full Text: https://doi.org/10.1212/wnl.40.9.1438]
Kupke, K. G., Lee, L. V., Viterbo, G. H., Arancillo, J., Donlon, T., Muller, U. X-linked recessive torsion dystonia in the Philippines. Am. J. Med. Genet. 36: 237-242, 1990. [PubMed: 2368812] [Full Text: https://doi.org/10.1002/ajmg.1320360219]
Lee, L. V., Pascasio, F. M., Fuentes, F. D., Viterbo, G. H. Torsion dystonia in Panay, Philippines. Adv. Neurol. 14: 137-151, 1976. [PubMed: 941767]
Makino, S., Kaji, R., Ando, S., Tomizawa, M., Yasuno, K., Goto, S., Matsumoto, S., Tabuena, M. D., Maranon, E., Dantes, M., Lee, L. V., Ogasawara, K., Tooyama, I., Akatsu, H., Nishimura, M., Tamiya, G. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am. J. Hum. Genet. 80: 393-406, 2007. [PubMed: 17273961] [Full Text: https://doi.org/10.1086/512129]
Muller, U., Haberhausen, G., Wagner, T., Fairweather, N. D., Chelly, J., Monaco, A. P. DXS106 and DXS559 flank the X-linked dystonia-parkinsonism syndrome locus (DYT3). Genomics 23: 114-117, 1994. [PubMed: 7829058] [Full Text: https://doi.org/10.1006/geno.1994.1465]
Muller, U., Lee, L. V., Viterbo, G., Arancillo, J., Caballar-Gonzaga, F., Hebron-Ortiz, M., Kupke, K. G. The phenotype of X-linked torsion dystonia (XLTD). (Abstract) Am. J. Hum. Genet. 47 (suppl.): A69 only, 1990.
Nemeth, A. H., Nolte, D., Dunne, E., Niemann,, S., Kostrzewa, M., Peters, U., Fraser, E., Bochukova, E., Butler, R., Brown, J., Cox, R. D., Levy, E. R., Ropers, H. H., Monaco, A. P., Muller, U. Refined linkage disequilibrium and physical mapping of the gene locus for X-linked dystonia-parkinsonism (DYT3). Genomics 60: 320-329, 1999. [PubMed: 10493831] [Full Text: https://doi.org/10.1006/geno.1999.5929]
Nolte, D., Niemann, S., Muller, U. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. Proc. Nat. Acad. Sci. 100: 10347-10352, 2003. [PubMed: 12928496] [Full Text: https://doi.org/10.1073/pnas.1831949100]
Nolte, D., Ramser, J., Niemann, S., Lehrach, H., Sudbrak, R., Muller, U. ACRC codes for a novel nuclear protein with unusual acidic repeat tract and maps to DYT3 (dystonia parkinsonism) critical interval in Xq13.1. Neurogenetics 3: 207-213, 2001. [PubMed: 11714101] [Full Text: https://doi.org/10.1007/s100480100120]
Wilhelmsen, K. C., Weeks, D. E., Nygaard, T. G., Moskowitz, C. B., Rosales, R. L., dela Paz, D. C., Sobrevega, E. E., Fahn, S., Gilliam, T. C. Genetic mapping of 'Lubag' (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome. Ann. Neurol. 29: 124-131, 1991. [PubMed: 1672807] [Full Text: https://doi.org/10.1002/ana.410290203]