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Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.
Aneichyk, Tatsiana; Hendriks, William T; Yadav, Rachita; Shin, David; Gao, Dadi; Vaine, Christine A; Collins, Ryan L; Domingo, Aloysius; Currall, Benjamin; Stortchevoi, Alexei; Multhaupt-Buell, Trisha; Penney, Ellen B; Cruz, Lilian; Dhakal, Jyotsna; Brand, Harrison; Hanscom, Carrie; Antolik, Caroline; Dy, Marisela; Ragavendran, Ashok; Underwood, Jason; Cantsilieris, Stuart; Munson, Katherine M; Eichler, Evan E; Acuña, Patrick; Go, Criscely; Jamora, R Dominic G; Rosales, Raymond L; Church, Deanna M; Williams, Stephen R; Garcia, Sarah; Klein, Christine; Müller, Ulrich; Wilhelmsen, Kirk C; Timmers, H T Marc; Sapir, Yechiam; Wainger, Brian J; Henderson, Daniel; Ito, Naoto; Weisenfeld, Neil; Jaffe, David; Sharma, Nutan; Breakefield, Xandra O; Ozelius, Laurie J; Bragg, D Cristopher; Talkowski, Michael E.
Afiliação
  • Aneichyk T; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Camb
  • Hendriks WT; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Yadav R; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Camb
  • Shin D; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Gao D; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Camb
  • Vaine CA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Collins RL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA.
  • Domingo A; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Camb
  • Currall B; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Stortchevoi A; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Multhaupt-Buell T; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Penney EB; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Cruz L; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Dhakal J; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Hanscom C; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Antolik C; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Dy M; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Ragavendran A; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Underwood J; Pacific Biosciences, Menlo Park, CA 94025, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Cantsilieris S; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Munson KM; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Eichler EE; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • Acuña P; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Go C; Jose Reyes Memorial Medical Center, Manila, Philippines.
  • Jamora RDG; Philippine General Hospital, Manila, Philippines.
  • Rosales RL; University of Santo Tomas Hospital, Manila, Philippines.
  • Church DM; 10X Genomics, Pleasanton, CA 94566, USA.
  • Williams SR; 10X Genomics, Pleasanton, CA 94566, USA.
  • Garcia S; 10X Genomics, Pleasanton, CA 94566, USA.
  • Klein C; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
  • Müller U; Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
  • Wilhelmsen KC; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Timmers HTM; German Cancer Consortium (DKTK) partner site Freiburg and Department of Urology, University Medical Center, Freiburg, Germany.
  • Sapir Y; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Wainger BJ; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Henderson D; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Ito N; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Weisenfeld N; 10X Genomics, Pleasanton, CA 94566, USA; Genome Sequencing and Analysis Program, Broad Institute, Cambridge, MA 02142, USA.
  • Jaffe D; 10X Genomics, Pleasanton, CA 94566, USA; Genome Sequencing and Analysis Program, Broad Institute, Cambridge, MA 02142, USA.
  • Sharma N; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Breakefield XO; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Ozelius LJ; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • Bragg DC; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA. Electronic address: bragg@helix.mgh.harvard.edu.
  • Talkowski ME; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Camb
Cell ; 172(5): 897-909.e21, 2018 02 22.
Article em En | MEDLINE | ID: mdl-29474918
ABSTRACT
X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Humano / Distúrbios Distônicos / Doenças Genéticas Ligadas ao Cromossomo X / Transcriptoma Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Genoma Humano / Distúrbios Distônicos / Doenças Genéticas Ligadas ao Cromossomo X / Transcriptoma Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: Cell Ano de publicação: 2018 Tipo de documento: Article