Group Lehesjoki

Molecular Basis of Epilepsy

Our 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.

A central focus of research is on disease mechanisms of progressive myoclonus epilepsy EPM1 utilizing cystatin B –deficient (Cstb-/-) mice as a model. We previously showed that cystatin B has a role in regulating neuronal survival during oxidative stress, which is at least partly mediated by cathepsin B signaling. More recently, we demonstrated that early microglial activation and neuroinflammation centrally contribute to neuronal dysfunction and death in Cstb-/- mice. We are currently investigating the molecular mechanisms associated with microglial activation and dysfunction, a long-term aim being the identification of novel target molecules and the development of anti-inflammatory therapies.

Gene identification is focused on progressive myoclonus epilepsy (PME) syndromes and severe early childhood-onset progressive encephalopathies using exome sequencing. The group recently reported identification of a recurrent de novo mutation in KCNC1 causing a dominant-negative loss-of-function effect on the KV3 voltage-gated potassium channel as a major underlying cause of PME worldwide. The group is also involved in analysis of the molecular genetics basis of generalized genetic epilepsies, which are multifactorial in origin. 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 Scientist

Tarja Joensuu, PhD

Clinical Scientists

Anna-Kaisa Anttonen, MD, PhD

Tarja Linnankivi, MD, PhD

Post-Doctoral Scientists

Carolina Courage, MD

Mikko Muona, PhD

Saara Tegelberg, PhD

Graduate Students

Eduard Daura Sarroca, MSc

Katarin Gorski, MSc

Anni Laari, MSc

Undergraduate Students

Henna Kallo, BSc

Erika Kuosa, Med Stud

Viivi Nevanlinna, Med Stud

Staff

Paula Hakala, Laboratory Nurse

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]

Folkhälsan Research Foundation

University of Helsinki

Sigrid Jusélius Foundation

Medicinska understödsföreningen Liv och Hälsa (“Life and Health Medical Fund”)

Prof. Sam Berkovic, University of Melbourne, Australia / co-coordinator of the PME genetics consortium

EuroEpinomics CoGIE and RES consortia, Epi25 consortium

Prof. Annamaria Vezzani, Mario Negri Institute for Pharmacological Research, Milan, Italy

Prof. Amanda Sierra, University of the Basque Country, Leioa, Spain

Prof. Esa Korpi, University of Helsinki

Prof. Kari Eklund, University of Helsinki

Prof. Reetta Kälviäinen, University of Eastern Finland

Doc. Maija Wessman, Folkhälsan Research Center

Prof. Juha Kere, Folkhälsan Research Center and Karolinska Institute

    • Anna-Elina Lehesjoki

      Professor

    • Tel:
      +358 29 412 5072 or +358 50 448 4729

    • Research Director at Folkhälsan Research Center

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