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The TAF1/DYT3 Multiple Transcript System in X-Linked Dystonia-Parkinsonism

2007; Elsevier BV; Volume: 81; Issue: 2 Linguagem: Inglês

10.1086/519528

1537-6605

Ulrich Müller, Thilo Herzfeld, Dagmar Nolte,

Neurological diseases and metabolism

To the Editor: The X-linked dystonia-parkinsonism syndrome (XDP or DYT3 [MIM #314250]) is a severe adult-onset movement disorder that originated by founder effect in the Philippine island of Panay.1Kupke KG Lee LV Viterbo GH Arancillo J Donlon T Müller U X-linked recessive torsion dystonia in the Philippines.Am J Med Genet. 1990; 36: 237-242Crossref PubMed Scopus (30) Google Scholar The disease gene was identified in 2003 and was described as a “multiple transcript system.” It is composed of several of the 38 known TAF1 (TATA-box binding protein–associated factor 1) exons and an additional 5 of the then-unknown exons that lie 3′ of TAF1 exon 38.2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar The latter five exons can either be spliced to known TAF1 exons (variants 1 and 2) or be transcribed separately (variants 3 and 4). Five disease-specific single-nucleotide changes (DSCs) and a small deletion were detected within this transcript system. One of the DSCs (DSC3) is located in a transcribed exon. These findings have now been confirmed by Makino and coworkers in the March issue of the Journal.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Whereas, in the original study, the DYT3 critical region was sequenced by PCR in a patient, Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar resequenced this region in BAC clones constructed from a patient’s DNA. The resequencing confirmed the DSCs described elsewhere2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar and detected a previously unrecognized retrotransposon (SVA [SINE, VNTR, and Alu] element) in intron 32 of TAF1 in close proximity to DSC10. Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar also confirmed the various splice variants of TAF1 that were found earlier.2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar Furthermore, the study by Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar validates our use of several DSCs in the routine molecular genetic diagnosis of XDP.4Evidente VGH X-linked dystonia-parkinsonism syndrome.Gene Reviews. 2005; (accessed June 8, 2007)(http://www.genetests.org/servlet/access?qry=evidente&submit=Search&id=8888891&prg=j&db=genestar&site=gc&fcn=author&key=2ufeYApfIefX3)Google Scholar It is currently not known whether or to what extent the DSCs in TAF1/DYT3 are involved in the disease process. Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar implicate the SVA retrotransposon in intron 32 of TAF1 in the pathology of XDP. They present several findings supporting an important role for SVA in XDP. In particular, they provide evidence that the SVA affects expression of a transcript splice variant described elsewhere2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar that includes exon 34′ of TAF1. However, the data are not entirely convincing.1. The article by Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar implies that there is only one splice variant of TAF1 that includes exon 34′. This is not accurate. There are other splice variants of TAF1 that also include exon 34′—for example, splice variants including exons 34′ and 32′ and splice variants including exons 34′, 3, and 4.2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar2. Figure 5a in the work of Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar shows dramatic reduction of expression of an exon 34′–containing transcript but also demonstrates reduced expression of the common form of TAF1 in a patient’s caudate nucleus. Although antibodies were directed against TAF1 polypeptides (and not specifically against the exon 34′ isoform), their figure 5f implies complete absence of TAF1 in the patient’s caudate. This cannot be explained by gliosis alone, since calcineurin antibodies definitely identified neurons in the patient’s caudate (see their figure 5f).3. Although hypermethylation was shown at CpG sites of SVA, a correlation between this epigenetic modification and the postulated specifically reduced expression of the exon 34′ transcript was not shown.4. When postmortem brain is used for the quantitative ascertainment of gene expression, a high degree of variation has to be kept in mind. Apart from biological reasons, different postmortem times, storage conditions, etc. account for this variation. This might explain why transcript variant 34′ of TAF1 is specifically reduced in some experiments but the common form of TAF1 is also affected in others (their fig. 5a and 5f).5. Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar(p402) indicate that the decrease in expression of the exon 34′ transcript is “the cause rather than the result of neuronal loss in the caudate nucleus….” This argument is not entirely convincing, since this transcript is also reduced in cortex and nucleus accumbens that do not show major neuronal loss. Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar do not provide evidence of neuronal subtype-specific expression and function of the exon 34′ transcript that might explain the discrepancy. Obviously, the molecular pathological mechanism in XDP remains unknown. The involvement of one or several of the described DSCs, either alone or in concert with the SVA retrotransposon, certainly cannot be ruled out. Here, a function of DSC3 is intriguing, since it is located in an exon that can be part of all major splice variants of the TAF1/DYT3 transcript system. However, intronic SNPs can also affect gene expression, as was recently shown with the SORL1 susceptibility gene for late-onset Alzheimer disease.5Rogaeva E Meng Y Lee JH Gu Y Kawarai T Zou F Katayama T Baldwin CT Cheng R Hasegawa H et al.The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.Nat Genet. 2007; 39: 168-177Crossref PubMed Scopus (824) Google Scholar Several other aspects of the article need further clarification. In figure 3, patients are shown carrying the “disease-specific” 6.1-kb SVA fragment, but other patients (right panel of fig. 3) show the “wild-type” fragment. Can the SVA fragment occur in healthy persons as well, or has a sample mix-up occurred? Makino et al.3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar claim that exon 2, described elsewhere2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar (3′ of TAF1 exon 38), is derived from ING2. This is not the case, since the ING2 pseudogene overlaps with exon 2 on the opposite strand. Exon 38 of TAF1 is skipped when further 3′ exons are used in a transcript. This was shown in cDNAs isolated from a brain cDNA bank and in RT-PCR experiments.2Nolte D Niemann S Müller U Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.Proc Natl Acad Sci USA. 2003; 100: 10347-10352Crossref PubMed Scopus (93) Google Scholar Makino et al.,3Makino S Kaji R Ando S Tomizawa M Yasuno K Goto S Matsumoto S Tabuena D Maranon E Dantes M et al.Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.Am J Hum Genet. 2007; 80: 393-406Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar however, report the presence of this exon in these alternative transcripts. Provided that this is no RT-PCR artifact, this does not disprove previous findings of the absence of exon 38 in some splice variants that include additional 3′ exons. In conclusion, many issues remain unresolved as to both the normal function of TAF1 variants in various tissues and the role of disease-specific changes in the TAF1/DYT3 multiple transcript system in patients with XDP. Our work was supported by Deutsche Forschungsgemeinschaft grant Mu668/12.