[en] Dystonia due to pathogenic variants in the THAP1 gene (DYT-THAP1) shows variable expressivity and reduced penetrance of ~ 50%. Since THAP1 encodes a transcription factor, modifiers influencing this variability likely operate at the gene expression level. This study aimed to assess the transferability of differentially expressed genes (DEGs) in neuronal cells related to pathogenic variants in the THAP1 gene, which were previously identified by transcriptome analyses. For this, we performed quantitative (qPCR) and Digital PCR (dPCR) in cultured fibroblasts. RNA was extracted from THAP1 manifesting (MMCs) and non-manifesting mutation carriers (NMCs) as well as from healthy controls. The expression profiles of ten of 14 known neuronal DEGs demonstrated differences in fibroblasts between these three groups. This included transcription factors and targets (ATF4, CLN3, EIF2A, RRM1, YY1), genes involved in G protein-coupled receptor signaling (BDKRB2, LPAR1), and a gene linked to apoptosis and DNA replication/repair (CRADD), which all showed higher expression levels in MMCs and NMCs than in controls. Moreover, the analysis of genes linked to neurological disorders (STXBP1, TOR1A) unveiled differences in expression patterns between MMCs and controls. Notably, the genes CUEDC2, DRD4, ECH1, and SIX2 were not statistically significantly differentially expressed in fibroblast cultures. With > 70% of the tested genes being DEGs also in fibroblasts, fibroblasts seem to be a suitable model for DYT-THAP1 research despite some restrictions. Furthermore, at least some of these DEGs may potentially also serve as biomarkers of DYT-THAP1 and influence its penetrance and expressivity.
Disciplines :
Genetics & genetic processes
Author, co-author :
Diaw, Sokhna Haissatou; Institute of Neurogenetics, University of Lübeck, 23562, Lübeck, Germany
DELCAMBRE, Sylvie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Molecular and Functional Neurobiology > Team Anne GRÜNEWALD
Much, Christoph; Institute of Neurogenetics, University of Lübeck, 23562, Lübeck, Germany
Ott, Fabian; Institute of Experimental Dermatology and Institute of Cardiogenetics, University of Lübeck, 23562, Lübeck, Germany
Kostic, Vladimir S; Institute of Neurology, School of Medicine, University of Belgrade, Belgrade, 11000, Serbia
Gajos, Agata; Department of Extrapyramidal Diseases, Medical University of Lodz, Lodz, 90-647, Poland
Münchau, Alexander; Institute of Systems Motor Science, University of Lübeck, 23562, Lübeck, Germany
Zittel, Simone; Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Busch, Hauke; Institute of Experimental Dermatology and Institute of Cardiogenetics, University of Lübeck, 23562, Lübeck, Germany
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Klein, Christine; Institute of Neurogenetics, University of Lübeck, 23562, Lübeck, Germany
Lohmann, Katja ; Institute of Neurogenetics, University of Lübeck, 23562, Lübeck, Germany. katja.lohmann@uni-luebeck.de
External co-authors :
yes
Language :
English
Title :
DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery.
Publication date :
April 2024
Journal title :
Neurogenetics
ISSN :
1364-6745
eISSN :
1364-6753
Publisher :
Springer Science and Business Media Deutschland GmbH, United States
FNR14429377 - Reduced Penetrance In Hereditary Movement Disorders: Elucidating Mechanisms Of Endogenous Disease Protection, 2020 (01/07/2020-30/06/2023) - Anne Grünewald
Funders :
Deutsche Forschungsgemeinschaft Luxembourgish Research Fund
Funding text :
This work was supported by research grants from the German Research Foundation (FOR2488. LO1555/9 − 2) and the Luxembourgish Research Fund (INTER/DFG/19/14429377).
S. Fahn S.B. Bressman C.D. Marsden Classification of dystonia Adv Neurol 1998 78 1 10 1:STN:280:DyaK1cvitlCksw%3D%3D 9750897
A. Albanese K. Bhatia S.B. Bressman et al. Phenomenology and classification of dystonia: a consensus update Mov Disord off J Mov Disord Soc 2013 28 863 873 10.1002/mds.25475
M. Thomsen L.M. Lange M. Zech K. Lohmann Genetics and Pathogenesis of Dystonia Annu Rev Pathol Mech Dis 2024 19 null 1:CAS:528:DC%2BB3sXhvFyqsrfK 10.1146/annurev-pathmechdis-051122-110756
L.M. Lange J. Junker S. Loens et al. Genotype–phenotype relations for isolated dystonia genes: MDSGene systematic review Mov Disord 2021 36 1086 1103 1:CAS:528:DC%2BB3MXhs1Cmtr7P 10.1002/mds.28485 33502045
S.B. Bressman D. Raymond T. Fuchs et al. THAP1 (DYT6) mutations in early-onset primary dystonia Lancet Neurol 2009 8 441 446 1:CAS:528:DC%2BD1MXlsVajsLg%3D 10.1016/S1474-4422(09)70081-X 19345147 3712754
H. Baumann F. Ott J. Weber et al. Linking penetrance and transcription in DYT-THAP1: insights from a human iPSC-Derived cortical model Mov Disord 2021 36 1381 1391 1:CAS:528:DC%2BB3MXhvFersL3N 10.1002/mds.28506 33547842
M. Roussigne S. Kossida A.-C. Lavigne et al. The THAP domain: a novel protein motif with similarity to the DNA-binding domain of P element transposase Trends Biochem Sci 2003 28 66 69 1:CAS:528:DC%2BD3sXptlyhtA%3D%3D 10.1016/S0968-0004(02)00013-0 12575992
D. Bessière C. Lacroix S. Campagne et al. Structure-function analysis of the THAP Zinc Finger of THAP1, a large C2CH DNA-binding Module Linked to Rb/E2F pathways * J Biol Chem 2008 283 4352 4363 10.1074/jbc.M707537200 18073205
Z. Zakirova T. Fanutza J. Bonet et al. Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions PLOS Genet 2018 14 e1007169 1:CAS:528:DC%2BC1cXhs1Ohs7nO 10.1371/journal.pgen.1007169 29364887 5798844
S.H. Diaw F. Ott A. Münchau et al. Emerging role of a systems biology approach to elucidate factors of reduced penetrance: transcriptional changes in THAP1-linked dystonia as an example Med Genet 2022 34 131 141 1:CAS:528:DC%2BB38Xit1WhsL3E 10.1515/medgen-2022-2126
F.J. Kaiser A. Osmanoric A. Rakovic et al. The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6) Ann Neurol 2010 68 554 559 1:CAS:528:DC%2BC3cXhsVOrur%2FN 10.1002/ana.22157 20976771
G. Xiromerisiou H. Houlden N. Scarmeas et al. THAP1 mutations and Dystonia phenotypes: genotype phenotype correlations Mov Disord 2012 27 1290 1294 1:CAS:528:DC%2BC38Xhs1Ghtr3N 10.1002/mds.25146 22903657 3664430
M. Ruiz G. Perez-Garcia M. Ortiz-Virumbrales et al. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia Hum Mol Genet 2015 24 7159 7170 1:CAS:528:DC%2BC28XmvFGis7s%3D 10.1093/hmg/ddv384 26376866 4757965
A. Gajos E. Golańska M. Sieruta et al. High variability of clinical symptoms in a Polish family with a novel THAP1 mutation Int J Neurosci 2015 125 755 759 1:CAS:528:DC%2BC2MXhsl2ntLfM 10.3109/00207454.2014.981749 25385508
K.J. Livak T.D. Schmittgen Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method Methods San Diego Calif 2001 25 402 408 1:CAS:528:DC%2BD38XhtFelt7s%3D 10.1006/meth.2001.1262 11846609
G. Tellmann The E-Method: a highly accurate technique for gene-expression analysis Nat Methods 2006 3 i ii 1:CAS:528:DC%2BD28XmtVSntr0%3D 10.1038/nmeth894
A. Erogullari R. Hollstein P. Seibler et al. THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression Biochim Biophys Acta BBA - Gene Regul Mech 2014 1839 1196 1204 1:CAS:528:DC%2BC2cXht1OqsLfF 10.1016/j.bbagrm.2014.07.019
J. Xian S. Parthasarathy S.M. Ruggiero et al. Assessing the landscape of STXBP1-related disorders in 534 individuals Brain 2022 145 1668 1683 10.1093/brain/awab327 35190816
Y. Fan Z. Si L. Wang L. Zhang DYT-TOR1A dystonia: an update on pathogenesis and treatment Front Neurosci 2023 17 1216929 10.3389/fnins.2023.1216929 37638318 10448058
R. Hollstein B. Reiz L. Kötter et al. Dystonia-causing mutations in the transcription factor THAP1 disrupt HCFC1 cofactor recruitment and alter gene expression Hum Mol Genet 2017 26 2975 2983 1:CAS:528:DC%2BC1cXjt1Sqsb8%3D 10.1093/hmg/ddx187 28486698
F. Cheng M. Walter Z. Wassouf et al. Unraveling Molecular mechanisms of THAP1 missense mutations in DYT6 dystonia J Mol Neurosci 2020 70 999 1008 1:CAS:528:DC%2BB3cXktFeltbg%3D 10.1007/s12031-020-01490-2 32112337 7334247
D. Yellajoshyula C.-C. Liang S.S. Pappas et al. The DYT6 dystonia protein THAP1 regulates myelination within the Oligodendrocyte lineage Dev Cell 2017 42 52 67e4 1:CAS:528:DC%2BC2sXhtFGmsLjF 10.1016/j.devcel.2017.06.009 28697333 5847273
J.E. Rittiner Z.F. Caffall R. Hernández-Martinez et al. Functional genomic analyses of mendelian and sporadic disease identify impaired eIF2α signaling as a generalizable mechanism for Dystonia Neuron 2016 92 1238 1251 1:CAS:528:DC%2BC28XitVOltrrE 10.1016/j.neuron.2016.11.012 27939583 5320521
S.B. Burnett L.S. Vaughn N. Sharma et al. Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2α signaling leading to a compromised stress response Neurobiol Dis 2020 146 105135 1:CAS:528:DC%2BB3cXitFeqsrfK 10.1016/j.nbd.2020.105135 33049316
P.M. Pitale O. Gorbatyuk M. Gorbatyuk Neurodegeneration: keeping ATF4 on a tight leash Front Cell Neurosci 2017 11 410 1:CAS:528:DC%2BC1cXisValtr%2FE 10.3389/fncel.2017.00410 29326555 5736573
D. Xiao X. Su H. Gao et al. The roles of Lpar1 in Central Nervous System disorders and diseases Front Neurosci 2021 15 710473 10.3389/fnins.2021.710473 34385905 8353257
S. Pabian-Jewuła A. Bragiel-Pieczonka M. Rylski Ying Yang 1 engagement in brain pathology J Neurochem 2022 161 236 253 1:CAS:528:DC%2BB38XmtlCjtLk%3D 10.1111/jnc.15594 35199341
C. Petrella M.T. Ciotti R. Nisticò et al. Involvement of bradykinin receptor 2 in nerve growth factor neuroprotective activity Cells 2020 9 2651 1:CAS:528:DC%2BB3MXnvFyiu7s%3D 10.3390/cells9122651 33321704 7763563
M. Bellin M.C. Marchetto F.H. Gage C.L. Mummery Induced pluripotent stem cells: the new patient? Nat Rev Mol Cell Biol 2012 13 713 726 1:CAS:528:DC%2BC38XhsVGjsLzI 10.1038/nrm3448 23034453
G. Miskinyte K. Devaraju M. Grønning Hansen et al. Direct conversion of human fibroblasts to functional excitatory cortical neurons integrating into human neural networks Stem Cell Res Ther 2017 8 207 1:CAS:528:DC%2BC1cXls1Glu70%3D 10.1186/s13287-017-0658-3 28962665 5622454
Y. Yang R. Chen X. Wu et al. Rapid and efficient Conversion of human fibroblasts into functional neurons by small molecules Stem Cell Rep 2019 13 862 876 1:CAS:528:DC%2BC1MXitVSjsL7E 10.1016/j.stemcr.2019.09.007
M.S. LeDoux J. Xiao M. Rudzińska et al. Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases Parkinsonism Relat Disord 2012 18 414 425 10.1016/j.parkreldis.2012.02.001 22377579 3358360
Y. Yang J. Wang F. Shi et al. BDKRB2 is a novel EMT-related biomarker and predicts poor survival in glioma Aging 2021 13 7499 7516 1:CAS:528:DC%2BB3MXhsFaltbnJ 10.18632/aging.202614 33686021 7993731
N.M. Frederick P.V. Shah A. Didonna et al. Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes Hum Mol Genet 2019 28 1343 1356 1:CAS:528:DC%2BC1MXitVeisr7O 10.1093/hmg/ddy433 30590536
S.L. Cotman J.F. Staropoli The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-golgi trafficking Clin Lipidol 2012 7 79 91 1:CAS:528:DC%2BC38XitFSns7Y%3D 10.2217/clp.11.70 22545070 3334816
N. Di Donato Y.Y. Jean A.M. Maga et al. Mutations in CRADD result in reduced caspase-2-Mediated neuronal apoptosis and cause Megalencephaly with a rare lissencephaly variant Am J Hum Genet 2016 99 1117 1129 1:CAS:528:DC%2BC28XhslemtrvP 10.1016/j.ajhg.2016.09.010 27773430 5097945
M. Koprulu R.M.K. Shabbir Q. Zaman et al. CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies Eur J Med Genet 2021 64 104181 1:CAS:528:DC%2BB38XitVWgs7rJ 10.1016/j.ejmg.2021.104181 33647455
S. Dipanwita B. Arindam B. Atanu et al. Genetic polymorphisms in DRD4 and risk for Parkinson’s Disease among Eastern indians Neurol India 2022 70 729 732 10.4103/0028-3886.344670 35532648
M.J.R.J. Taj B. Viswanath M. Purushottam et al. DRD4 gene and obsessive compulsive disorder: do symptom dimensions have specific genetic correlates? Prog Neuropsychopharmacol Biol Psychiatry 2013 41 18 23 1:CAS:528:DC%2BC3sXhsV2jtb0%3D 10.1016/j.pnpbp.2012.10.023
J. Long G. Pan E. Ifeachor et al. Discovery of Novel biomarkers for Alzheimer’s Disease from blood Dis Markers 2016 2016 4250480 1:CAS:528:DC%2BC2sXnsFGlu7Y%3D 10.1155/2016/4250480 27418712 4932164
D. Huang B. Liu K. Huang K. Huang Enoyl coenzyme a hydratase 1 protects against high-fat-diet-induced hepatic steatosis and insulin resistance Biochem Biophys Res Commun 2018 499 403 409 1:CAS:528:DC%2BC1cXmvFKhtbc%3D 10.1016/j.bbrc.2018.03.052 29526751
S. Bond C. Lopez-Lloreda P.J. Gannon et al. The Integrated Stress Response and phosphorylated eukaryotic initiation factor 2α in Neurodegeneration J Neuropathol Exp Neurol 2020 79 123 143 1:CAS:528:DC%2BB3cXit1amtL%2FK 10.1093/jnen/nlz129 31913484 6970450
J. Shintaku W.M. Pernice W. Eyaid et al. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis J Clin Invest 2022 132 e145660 1:CAS:528:DC%2BB38Xit1ersrbM 10.1172/JCI145660 35617047 9246377
C. Zhang D. Qin X. Cao et al. Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1 expression iScience 2023 26 107049 1:CAS:528:DC%2BB3sXhtlCqu77F 10.1016/j.isci.2023.107049 37534182 10391717
H. Stamberger M. Nikanorova M.H. Willemsen et al. STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy Neurology 2016 86 954 962 1:CAS:528:DC%2BC28XktVOju70%3D 10.1212/WNL.0000000000002457 26865513
R. Spaull D. Steel K. Barwick et al. STXBP1 Stop-Loss Mutation Associated with Complex Early Onset Movement Disorder without Epilepsy Mov Disord Clin Pract 2022 9 837 840 10.1002/mdc3.13509 35937496 9346254
J.T. Cunningham J.T. Rodgers D.H. Arlow et al. mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex Nature 2007 450 736 740 1:CAS:528:DC%2BD2sXhtlKmtb3K 10.1038/nature06322 18046414
I. Mizuta K. Takafuji Y. Ando et al. YY1 binds to α-synuclein 3′-flanking region SNP and stimulates antisense noncoding RNA expression J Hum Genet 2013 58 711 719 1:CAS:528:DC%2BC3sXhvVOhsr%2FE 10.1038/jhg.2013.90 24026176
Z.S. Chen H.Y.E. Chan Transcriptional dysregulation in neurodegenerative diseases: who tipped the balance of Yin Yang 1 in the brain? Neural Regen Res 2019 14 1148 1151 1:CAS:528:DC%2BB38XhvFChsb7F 10.4103/1673-5374.251193 30804239 6425841
