Our group studies a variety of neurological disorders including epilepsy, intellectual disability and autism spectrum disorders. These disorders each have a strong genetic basis and some are associated with abnormal growths in the brain such as tubers and cortical malformations, which have features similar to tumours. We employ a number of different methods to identify the genetic cause of these disorders in patients. Some of these patients are from families with a history of the disorder while others are isolated cases. The strategies we use include genetic linkage, genome and exome sequencing and targeted re-sequencing of specific genes along with bioinformatics analysis. We have discovered a number of genes involved in neurological disorders including PCDH19 in epilepsy and intellectual disability in females, KCNT1 in focal epilepsy with psychiatric features and DEPDC5 in focal epilepsies with or without brain malformations. We also use animal models including Drosophila and Mouse to understand the biological processes by which mutations in these genes lead to neurological disorders. Such knowledge will assist in developing improved treatments for patients.
Current research projects
- Identifying new genes in neurological disorders. We have a large number of families and patients affected with various forms of, for example, epilepsy where we have not yet identified the gene responsible. In this project multiplex families will be analysed by exome sequencing and bioinformatics analysis to identify the causative gene. Once a gene is identified we confirm the finding by looking for further mutations in additional patients with a similar phenotype. We can then begin to investigate any genotype-phenotype correlations.
- Using Drosophila to understand the biology of neurological disorders. Drosophila melanogaster is a powerful model organism which allows sophisticated genetic manipulation directed at revealing the function of uncharacterised genes. This project will utilise Drosophila to overexpress, knockout or alter expression of a particular gene. This allows us to explore the role of our newly identified genes in neurological disorders to identify which gene pathways they act in and how perturbation of their function results in human disease. We also use Drosophila carrying these disease causing gene alterations as a means to screen for new drugs to treat these diseases.
- Mouse models of neurological disease. With the advent of new genome editing technologies it is possible to rapidly generate knockouts and knock-ins of genes that we have identified to be disease causing in our genetic studies in humans. Such knockout mice allow us to conduct powerful genetic and biochemical experiments to determine how these genes work and cause disease. Such knowledge of how genes work in vivo is vital in developing strategies to treat the diseases they cause.
Muona, M., Berkovic, S.F., Dibbens, L.M., Oliver, K.L., Maljevic, S., Bayly, M.A., Joensuu, T., Canafoglia, L., Franceschetti, S., Michelucci, R., Markkinen, S., Heron, S.E., Hildebrand, M.S., Andermann, E., Andermann, F., Gambardella, A., Tinuper, P., Licchetta, L., Scheffer, I.E., Criscuolo, C., Filla, A., Ferlazzo, E., Ahmad, J., Ahmad, A., Baykan, B., Said, E., Topcu, M., Riguzzi, P., King, M.D., Ozkara, C., Andrade, D.M., Engelsen, B.A., Crespel, A., Lindenau, M., Lohmann, E., Saletti, V., Massano, J., Privitera, M., Espay, A.J., Kauffmann, B., Duchowny, M., Møller, R.S., Straussberg, R., Afawi, Z., Ben-Zeev, B., Samocha, K.E., Daly, M.J., Petrou, S., Lerche, H., Palotie, A., Lehesjoki, A.E. “A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.” Nat Genet. doi: 10.1038/ng.3144. (2014).
Scheffer, I.E., Heron, S.E., Regan, B., Mandelstam, S., Crompton, D.E., Hodgson, B.L., Licchetta, L., Provini, F., Bisulli, F., Vadlamudi, L., Gecz, J., Connelly, A., Tinuper, P., Ricos, M.G., Berkovic, S.F., Dibbens, L.M. “Mutations in mTOR regulator DEPDC5 cause focal epilepsy with brain malformations.” Ann Neurol 75:782-787 (2014).
Dibbens, L.M., de Vries, B., Donatello, S., Heron, S.E., Hodgson, B.L., Chintawar, S., Crompton, D.E., Hughes, J.N., Bellows, S.T., Klein, K.M., Callenbach, P.M.C., Corbett, M.A., Gardner, A.E., Kivity, S., Iona, X., Regan, B.M., Weller, C.M., Crimmins ,D., O’Brien, T., Guerrero-López, R., Mulley, J.C., Dubeau, F., Licchetta, L., Bisulli, F., Cossette, P., Thomas, P.Q., Gecz, J., Serratosa, J., Brouwer, O.F., Andermann, F., Andermann, E., Maagdenberg, A.M.J.M., Pandolfo, M., Berkovic, S.F., Scheffer, I.E. “Mutations in DEPDC5 cause Familial Focal Epilepsy with Variable Foci.” Nat Gen 45:546-51 (2013).
Heron, S.E., Dibbens, L.M. “Role of PRRT2 in common paroxysmal neurological disorders: a gene with remarkable pleiotropy.” Review. J Med Genet 50:133-139 (2013).
Heron, S.E., Smith, K.R., Bahlo, M., Nobili, L., Kahana, E., Licchetta, L., Oliver, K.L., Mazarib, A., Afawi, Z., Korczyn, A., Plazzi, G., Petrou, S., Berkovic, S.F., Scheffer, I.E., Dibbens, L.M. “Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy.” Nat Genet. 44(11):1188-90. doi: 10.1038/ng.2440 (2012).
Heron, S.E., Grinton, B.E., Kivity, S., Afawi, Z., Zuberi, S.M., Hughes, J.N., Pridmore, C., Hodgson, B.L., Iona, X., Sadleir, L.G., Pelekanos, J., Herlenius, E., Goldberg-Stern, H., Bassan, H., Haan, E., Korczyn, A.D., Gardner, A.E., Corbett, M.A., Gécz, J., Thomas, P.Q., Mulley, J.C., Berkovic, S.F., Scheffer, I.E., Dibbens, L.M. “PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome.” Am J Hum Genet 90(1):152-60. doi: 10.1016/j.ajhg.2011.12.003. (2012).