Ana Westenberger1, Charles Jourdan Reyes1, Gerard Saranza2, Valerija Dobricic1,3, Henrike Hanssen1,4, Aloysius Domingo1,5, Björn-Hergen Laabs6, Susen Schaake1, Jelena Pozojevic7, Aleksandar Rakovic1, Karen Grütz1, Kimberly Begemann1, Uwe Walter8, Dirk Dressler9, Peter Bauer10, Arndt Rolfs10, Alexander Münchau1, Frank J Kaiser7, Laurie J Ozelius11, Roland Dominic Jamora2, Raymond L Rosales12, Cid Czarina E Diesta13, Katja Lohmann1, Inke R König6, Norbert Brüggemann1,4, Christine Klein1. 1. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. 2. Department of Neurosciences, College of Medicine-Philippine General Hospital, University of the Philippines, Manila, Philippines. 3. Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany. 4. Department of Neurology, University of Lübeck, Lübeck, Germany. 5. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA. 6. Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany. 7. Section for Functional Genetics, Institute for Human Genetics, University of Lübeck, Lübeck, Germany. 8. Department of Neurology, University of Rostock, Rostock, Germany. 9. Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover, Germany. 10. Centogene, Rostock, Germany. 11. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 12. University of Santo Tomas Hospital, Manila, Philippines. 13. Department of Neurosciences, Movement Disorders Clinic, Makati Medical Center, Makati City, Philippines.
Abstract
OBJECTIVE: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.
OBJECTIVE:X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.
Authors: Roland Dominic G Jamora; Cezar Thomas R Suratos; Jesi Ellen C Bautista; Gail Melissa I Ramiro; Ana Westenberger; Christine Klein; Lourdes K Ledesma Journal: J Neural Transm (Vienna) Date: 2021-02-27 Impact factor: 3.575
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Authors: Tiziana Petrozziello; Amanda M Dios; Kaly A Mueller; Christine A Vaine; William T Hendriks; Kelly E Glajch; Alexandra N Mills; Kotchaphorn Mangkalaphiban; Ellen B Penney; Naoto Ito; Cara Fernandez-Cerado; Gierold Paul A Legarda; M Salvie Velasco-Andrada; Patrick J Acuña; Mark A Ang; Edwin L Muñoz; Cid Czarina E Diesta; Regina Macalintal-Canlas; Geraldine Acuña; Nutan Sharma; Laurie J Ozelius; D Cristopher Bragg; Ghazaleh Sadri-Vakili Journal: PLoS One Date: 2020-12-14 Impact factor: 3.240
Authors: Olympia Gianfrancesco; Bethany Geary; Abigail L Savage; Kimberley J Billingsley; Vivien J Bubb; John P Quinn Journal: Int J Mol Sci Date: 2019-11-27 Impact factor: 5.923