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Reza Sailani, M.* ; Jahanbani, F.* ; Abbott, C.W.* ; Lee, H.* ; Zia, A.* ; Rego, S.* ; Winkelmann, J. ; Hopfner, F.* ; Khan, T.N.* ; Katsanis, N.* ; Müller, S.H.* ; Berg, D.* ; Lyman, K.M.* ; Mychajliw, C.* ; Deuschl, G.* ; Bernstein, J.A.* ; Kuhlenbäumer, G.* ; Snyder, M.P.*

Candidate variants in TUB are associated with familial tremor.

PLoS Genet. 16:e1009010 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Author summary Essential tremor (ET) is the most common adult-onset movement disorder and in most affected families it appears to be inherited in an autosomal dominant pattern. The causes of essential tremor are unknown. Although many genetic studies in affected families and sporadic cases of ET have shown that genes may play a role, it has proven quite challenging to identify the specific genetic variants involved. Here, we use state-of-the-art technologies to identify the role of genetic variants on ET through exome sequencing of a large affected ET family and subsequent validation in a large population of cases and controls. We show that rare nonsynonymous variants of theTUBgene are significantly enriched in ET cases versus healthy controls. Further studies of biological pathways regulated by TUB in the mouse brain reveal key pathways related to ET. Our work expands our knowledge of the genetic basis of ET.Essential tremor (ET) is the most common adult-onset movement disorder. In the present study, we performed whole exome sequencing of a large ET-affected family (10 affected and 6 un-affected family members) and identified aTUBp.V431I variant (rs75594955) segregating in a manner consistent with autosomal-dominant inheritance. Subsequent targeted re-sequencing ofTUBin 820 unrelated individuals with sporadic ET and 630 controls revealed significant enrichment of rare nonsynonymousTUBvariants (e.g. rs75594955: p.V431I, rs1241709665: p.Ile20Phe, rs55648406: p.Arg49Gln) in the ET cohort (SKAT-O test p-value = 6.20e-08).TUBencodes a transcription factor predominantly expressed in neuronal cells and has been previously implicated in obesity. ChIP-seq analyses of the TUB transcription factor across different regions of the mouse brain revealed that TUB regulates the pathways responsible for neurotransmitter production as well thyroid hormone signaling. Together, these results support the association of rare variants inTUBwith ET.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Movement-disorders; Gene; Risk; Prevalence; Mutations; Receptors; Disease; Onset; Twins
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Journal PLoS Genetics
Quellenangaben Volume: 16, Issue: 9, Pages: , Article Number: e1009010 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
Grants SNSF
Swiss National Science Foundation (SNSF)
National Institutes of Health
DOI 10.1371/journal.pgen.1009010
WOS ID WOS:000574445300001
Scopus ID 85092236037
PubMed ID 32956375
Erfassungsdatum 2020-10-20
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