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A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism
Author(s) -
Westenberger Ana,
Reyes Charles Jourdan,
Saranza Gerard,
Dobricic Valerija,
Hanssen Henrike,
Domingo Aloysius,
Laabs BjörnHergen,
Schaake Susen,
Pozojevic Jelena,
Rakovic Aleksandar,
Grütz Karen,
Begemann Kimberly,
Walter Uwe,
Dressler Dirk,
Bauer Peter,
Rolfs Arndt,
Münchau Alexander,
Kaiser Frank J.,
Ozelius Laurie J.,
Jamora Roland Dominic,
Rosales Raymond L.,
Diesta Cid Czarina E.,
Lohmann Katja,
König Inke R.,
Brüggemann Norbert,
Klein Christine
Publication year - 2019
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25488
Subject(s) - dystonia , parkinsonism , expressivity , genetics , biology , medicine , disease , neuroscience
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.