Group Lehesjoki
Molecular Basis of EpilepsyOur research aims at understanding the molecular basis of epilepsy syndromes through identification of the underlying defective genes, followed by functional analyses of the gene products and characterization of disease mechanisms in cellular and animal models with the long-term aim of developing new therapies.
A central focus of research is on disease mechanisms of progressive myoclonus epilepsy EPM1 utilizing cystatin B -deficient (Cstb-/-) mice and patient-derived induced pluripotent stem cells (iPSC) as models. We previously showed that cystatin B has a role in regulating neuronal survival during oxidative stress and that early microglial activation and neuroinflammation centrally contribute to neuronal dysfunction and death in Cstb-/- mice. Our research currently focuses on investigating the nuclear function of cystatin B and molecular mechanisms associated with synaptic and microglial dysfunction. Within the Business Finland -supported “New Modalities Ecosystem” -project, coordinated by Orion, the group participates in the discovery of metabolic pathways contributing to progression of rare neurodegenerative diseases.
Gene identification is focused on progressive myoclonus epilepsy syndromes and severe early childhood-onset progressive encephalopathies using exome sequencing. The group recently identified KCNC1 as an important novel underlying cause of progressive myoclonus epilepsies worldwide and reported identification of three novel genes (UBA5, ADAM22, ZNHIT3) for progressive encephalopathies. Gene identification involves collaboration with large international consortia. The consortium aiming at deciphering the molecular genetic spectrum of PMEs is headed by the PI and Prof. Sam Berkovic in Melbourne.
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Senior Scientists
Tarja Joensuu, PhD, Administrative Group Leader
Saara Tegelberg, PhD
Clinical Scientists
Anna-Kaisa Anttonen, MD, PhD
Tarja Linnankivi, MD, PhD
Post-Doctoral Scientists
Carolina Courage, MD
Graduate Students
Eduard Daura Sarroca, MSc
Katarin Gorski, MSc
Staff
Paula Hakala, Laboratory Coordinator
Veronika Rezov, Laboratory Coordinator
Katri Aksentjeff, Research Assistant
Pennacchio LA, Lehesjoki A-E, Stone NE, Willour VL, Virtaneva K, Miao J, D'Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington J, Norio R, de la Chapelle A, Cox DR, Myers RM. Mutations in the gene encoding cystatin B cause progressive myoclonus epilepsy (EPM1). Science 271: 1731-1734, 1996
Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, Sharp J, Wheeler R, More S, Liu W, Soares MB, de Fatima Bonaldo M, Hirvasniemi A, de la Chapelle A, Gilliam TC, Lehesjoki A-E. The neuronal ceroid lipofuscinosis in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nature Genet 23: 233-236, 1999
Kolehmainen J, Black GCM, Saarinen A, Chandler K, Träskelin A-L, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns J-P, de la Chapelle A, Lehesjoki A-E. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet 72: 1359-1369, 2003
Lehtinen MK, Tegelberg S, Schipper H, Su H, Zukor H, Manninen O, Kopra O, Joensuu T, Hakala P, Bonni A, Lehesjoki A-E. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neurosci 29:5910-5915, 2009
Polvi A, Linnankivi T, Kivelä T, Herva R, Keating JP, Mäkitie O, Pareyson D, Vainionpää L, Lahtinen J, Hovatta I, Pihko H, Lehesjoki A-E. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet 90: 540-549, 2012
Tegelberg S, Kopra O, Joensuu T, Cooper JD, Lehesjoki A-E. Early microglial activation precedes neuronal loss in the brain of the Cstb-/- mouse model for progressive myoclonus epilepsy, EPM1. J Neuropathol Exp Neurol 71: 40-53, 2012
Okuneva O, Körber I, Li Z, Tian L, Joensuu T, Kopra O, Lehesjoki A-E. Abnormal microglial activation in the Cstb-/- mouse, a model for progressive myoclonus epilepsy, EPM1. Glia 63: 400-411, 2015
Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand M, Andermann E, Andermann F, Antonio Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DA, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben-Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki A-E. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nature Genet 47: 39-46, 2015
Muona M, Ishimura R, Laari A, Ichimura Y, Linnankivi T, Keski-Filppula R, Herva R, Rantala H, Paetau A, Pöyhönen M, Obata M, Uemura T, Karhu T, Bizen N, Takebayashi H, Anttonen A-K,14, Tanaka K, Palotie A, Waguri S, Lehesjoki A-E, Komatsu M. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier to severe infantile-onset encephalopathy. Am J Hum Genet 99: 683-694, 2016
Anttonen A-K, Laari A, Kousi M, Yang YJ, Jääskeläinen T, Somer M, Siintola E, Jakkula E, Muona M, Tegelberg S, Lönnqvist T, Pihko H, Valanne L, Paetau A, Hästbacka J, Kopra O, Joensuu T, Katsanis N, Lehtinen MK, Palvimo JJ, Lehesjoki A-E. ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with impaired cerebellar granule cell migration. Brain 2017 Mar 1. doi: 10.1093/brain/awx040. [Epub ahead of print]
Muona M, Fukata Y, Anttonen A-K, Laari A, Palotie A, Pihko H, Lönnqvist T, Valanne L, Somer M, Fukata M, Lehesjoki A-E. Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy. Neurol Genet 2: e46, 2016 (doi: 10.1212/NXG.0000000000000046)
Nevanlinna V, Konovalova S, Ceulemans B, Muona M, Laari A, Hilander T, Gorski K, Valanne L, Anttonen AK, Tyynismaa H, Courage C, Lehesjoki AE. A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome. Eur J Med Genet 103766, 2019 (doi:10.1016/j.ejmg.2019.103766)
Folkhälsan Research Foundation
University of Helsinki
Sigrid Jusélius Foundation
Medicinska understödsföreningen Liv och Hälsa (“Life and Health Medical Fund”)
Business Finland
Prof. Sam Berkovic, University of Melbourne, Australia / co-coordinator of the PME genetics consortium
EuroEpinomics CoGIE and RES consortia, Epi25 consortium
Prof. Amanda Sierra, University of the Basque Country, Leioa, Spain
Prof. Kari Eklund, University of Helsinki
Prof. Reetta Kälviäinen, University of Eastern Finland
Prof. Juha Kere, Folkhälsan Research Center and Karolinska Institute
Dr. Brendan Battersby, University of Helsinki
Dr. Christopher Jackson, University of Helsinki
Prof. Anu Wariovaara, University of Helsinki
