Epilepsy Research Program

The WCH began molecular studies in epilepsy in 1995 in collaboration with a clinical group in Melbourne headed by Professor Sam Berkovic. This quickly led to the localisation by linkage of a gene for nocturnal frontal lobe epilepsy and the identification of its causal gene, the alpha4 subunit of the acetylcholine receptor.

Subsequently a gene was identified for generalised epilepsy with febrile seizures plus (the ß1 subunit of the sodium channel), the second gene for nocturnal frontal lobe epilepsy (the ß2 subunit of the acetylcholine receptor), a gene for childhood absence epilepsy and febrile seizures (the GABRG2 subunit of the GABAA receptor) and a gene for familial neonatal-infantile seizures (the alpha2 subunit of the sodium channel). These findings have had a significant impact on establishing that epilepsy is a family of channelopathies.

Key personnel

Team Leader: Associate Professor John Mulley PhD FHGSA

Team Members

Leanne Dibbens PhD
Sarah Heron BSc(Hons)
Marta Bayly BBiotech (Hons)
Robert Schultz DipBiomedSci
Bree Hodgson DipBiomedSci
Xenia Iona DipBiomedSci
Tristiana Williams BSc
Beverley Johns CertMedTech

Selected publications

Phillips, H.A., Scheffer, I.E., Berkovic, S.F., Hollway, G.E., Sutherland, G.R., Mulley, J.C. (1995).  Localisation of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2.  Nature Genet 10: 117-118.

Steinlein, O.K., Mulley, J.C., Propping, P., Wallace, R., Phillips, H.A., Sutherland, G.R., Scheffer, I.E., Berkovic, S.F. (1995).  A missence mutation in the neuronal nicotinic acetylcholine receptor a4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.  Nature Genet 11: 201-203.

Wallace, R.H., Wang, D.W., Singh, R., Scheffer, I.E., George, A.L. Jr., Phillips, H.A., Saar, K., Reis, A., Johnson, E.W., Sutherland, G.R., Berkovic, S.F., Mulley, J.C. (1998).  Febrile seizures and generalised epilepsy is associated with a mutation in the Na+ channel B1 subunit gene SCN1B. Nature Genet 19: 366-370.

Phillips, H.A., Favre, I., Kirkpatrick, M., Zuberi, S.M., Goudie, D., Heron, S.E., Scheffer, I.E., Sutherland, G.R., Berkovic, S.F., Bertrand, D., Mulley, J.C. (2001).  CHRNB2 is the second acetylcholine receptor subunit associated with autosomal  dominant nocturnal frontal lobe epilepsy.  Am. J. Hum. Genet. 68: 225-231.  Wallace, R.H., Marini, C., Petrou, S., Harkin, L.A., Bowser, D.N., Panchal, R.G., Williams, D.A., Sutherland, G.R., Mulley, J.C., Scheffer, I.E., Berkovic, S.F. (2001).  Mutant GABAa receptor g2-subunit in childhood absence epilepsy and febrile seizures.  Nature Genet. 28: 49-52.

Harkin, L.A., Bowser, D.N., Dibbens, L.M., Singh, R., Phillips, F., Wallace, R.H., Richards, M.C., Williams, D.A., Mulley, J.C., Berkovic, S.F., Scheffer, I.E., Petrou, S. (2002).  Truncation of the GABAA receptor g2 subunit is associated with generalised epilepsy with febrile seizures plus.  Am J Hum Genet 70: 530-536.

Heron, S.E., Crossland, K.M., Andermann, E., Phillips, H.A., Hall, A.J., Bleasel, A., Shevall, M., Mercho, S., Seni, M-H., Guiot, M-C., Mulley, J.C., Berkovic, S.F., Scheffer, I.E. (2002).  Sodium-channel defects in benign familial neonatal-infantile convulsions.  Lancet 360: 851-852.

Berkovic, S.F., Heron, S.E., Giordano, L., Marini, C., Guerrini, R., Kaplan, R.E., Gambardella, A., Steinlein, O., Grinton, B., Dean, J.T., Bordo, L., Hodgson, B., Yamamoto, T., Mulley, J.C., Zara, F., Scheffer, I.E. (2004).  Benign familial neonatal-infantile seizures: characterisation of a new sodium channelopathy.  Ann Neurol 55: 550-557.

Dibbens, L.M., Feng, H., Richards, M.C., Harkin, L.A., Hodgson, B.L., Scott, D., Jenkins, M., Petrou, S., Sutherland G.R., Scheffer, I. E., Berkovic, S.F., MacDonald, R.L., Mulley, J.C. (2004).  GABRD encoding a protein for extrasynaptic GABAA receptors is a susceptibility locus for generalised epilepsies.  Hum Molec Genet 13:1315-1319.

Berkovic, S.F., Harkin, L., McMahon, J.M., Pelekanos M.B., Zuberi, S.M., Wirrell, E.C., Gill, D., Iona, X., Mulley, J.C., Scheffer, I.E. (2006).  De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study.  Lancet Neurol. 5: 488-492.

Mulley, J.C., Nelson, P., Guerrero, S., Dibbens, L.M., Iona, X., McMahon, J., Harkin, L.A., Schouten, J., Yu, S., Berkovic, S.F., Scheffer, I.E. (2006).  A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A. Neurology 67: 1094-1095.

Dibbens, L., Ekberg, J., Taylor, I.,  Hodgson, B.,  Conroy, S., Lensink, I.,Kumar, S., Zielinski, M., Harkin, L., Sutherland, G.R., Adams, D., Berkovic, S.,Scheffer, I.,  Mulley, J.C., Poronnik, P. (2007).  NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity.  Genes Brain Behav. 6: 750-755.

Harkin L.A., McMahon J.M., Iona, X., Dibbens, L., Pelekanos, J.T., Zuberi, S., Sadlier, L.G., Andermann, E., Gill. D., Farrell, K., Connolly, M., Stanley, T., Harboard, M., Andermann, F., Wang, J., Batish, S.D., Jones, J.G., Selter, W.K., Gardner, A., The Infantile Epileptic Referral Consortium, Sutherland, G.R., Berkovic, S.F., Mulley, J.C., Scheffer, I.E. (2007).  The spectrum of SCN1A-related infantile encephalopathies.  Brain 130: 843-852.

Heron, S.E., Cox, K., Grinton, B.E., Zuberi, S.M., Kivity, S., Afawi, Z., Straussberg, R., Berkovic, S.F., Scheffer,I.E., Mulley, J.C.  (2007). Exonic deletions and duplications of KCNQ2 in families with benign familial neonatal seizures. J Med Genet 44: 791-796.

Heron, S.E., Khosravini, H., Varela, D., Bladen, C., Williams, T.C., Newman, M.R., Scheffer, I.E., Berkovic, S.F., Mulley, J.C., Zamponi, G.  (2007).  Extended spectrum of idiopathic generalised epilepsies associated with CACNA1H functional variants.  Ann Neurol 62: 560-568.

Tan, H.O., Reid, C.A., Single, F.N., Davies, P., Chiu, C., Murphy, S., Clarke, A.L., Dibbens, L., Krestal, H., Mulley, J., Jones, M.V., Seeburg, P., Sakman, B., Berkovic, S.F., Sprengel, R., Petrou, S. (2007).  Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy.  Proc Natl Acad Sci USA 104: 17536-17541.

Berkovic, S.F., Dibbens, L.M., Oshlack, A., Silver, J.D., Katerelos, M., Vears, D.F., Lullmann-Rauch, R., Blanz, J., Zhang, K.W., Stankovic, J., Kalnins, R.M., Dowling, J.P., Andermann, E., Andermann, F., Faldini, E., D’Hooge, R., Vadlamudi, L., Macdonnell R.A., Hodgson, B.L., Bayly, M.A., Savige, J., Mulley, J.C., Smyth, G.K., Power, D.A., Saftig, P., Bahlo, M. (2008).  Myoclonus epilepsy and glomerulosclerosis due to deficiency of the lysosomal membrane protein SCARB2/Limp2. Am J Hum Genet 82: 673-684.

Dibbens, L.M., Tarpey, P.S., Hynes, K., Bayly, M.A., Scheffer, I.E., Smith, R., Bomar, J., Sutton, E., Vandeleur, L., Shoubridge, C., Edkins, S., Turner, S.J., Stevens, C., O’Meara, S., Tofts, C., Barthorpe, S., Buck, G., Cole, J., Halliday, K., Jones, D., Lee, R., Madison, M., Mironenko, T., Varian, J., West, S., Widaa, S., Wray, P., Teague, J., Dicks, E., Butler, A., Menzies, A., Jenkinson, A., Sheperd, R., Gusella, J.F., Afawi, Z., Mazarib, A., Neufeld, M.Y., Kivity, S., Lev, D., Lerman-Sagie, T., Korczyn, A.D., Derry, C.P., Sutherland, G.R., Friend, K., Shaw, M., Corbett, M., Hyong-Goo, K., Geschwind, D. H., Thomas, P., Haan, E., Ryan, S., McKee, S., Berkovic, S.F.,  Futreal, P.A., Stratton, M.R., Mulley, J.C., Gecz, J. (2008).  Protocadheron 19 mutations cause sex-limited epilepsy and cognitive impairment.  Nature Genet (In press).

Invited reviews

Mulley, J.C., Scheffer, I.E., Petrou, S., Berkovic, S. (2003).  Channelopathies as a genetic cause of epilepsy.  Curr Opin Neurol 16: 171-176.

Tan, N.C.K., Mulley, J.C., Berkovic, S.F. (2004).  Genetic association studies in epilepsy: “the truth is out there”.  Epilepsia 45: 1429-1442.

Mulley, J.C., Berkovic, S.F., Harkin, L.A., Scheffer, I.E. Dibbens, L.M (2005)  Susceptibility genes for complex epilepsy.  Hum Mol Genet 14: R243-R249.

Mulley, J.C., Scheffer, I.E., Petrou, S., Dibbens, L.M., Berkovic, S.F., Harkin, L.A. (2005).  SCN1A mutations and epilepsy.  Hum Mutat 25: 535-542.

Berkovic, S.F., Mulley, J.C., Scheffer, I.E., Petrou, S. (2006).  Human epilepsies: interaction of genetic and acquired factors.  Trends Neurosci. 29: 391-397.

Tan, N.C.K., Mulley, J.C., Scheffer, I.E. (2006).  Susceptibility genes for common epilepsies: 2006 update.  Curr. Opin. Neurol. 19: 157-163.

Dibbens, L.M., Heron, S.E., Mulley, J.C.  (2007). A polygenic heterogeneity model for complex epilepsy?  Genes Brain Behav. 6: 593-597.

Heron, S., Scheffer, I.E., Berkovic, S.F., Dibbens, L.M., Mulley, J.C. (2007).  Channelopathies in idiopathic epilepsy.  NeuroRx 4: 295-304.

Helbig, I., Scheffer, I.E., Mulley, J.C., Berkovic S.F. (2008). Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol 7: 231-245.

Contact Information

Unit Head

Team Leader

Associate Professor John Mulley PhD FHGSA

Location

Epilepsy Research Program
Department of Genetic Medicine
Level 9, Rieger Building
Women's and Children's Hospital
72 King William Road
North Adelaide
South Australia 5006

Mailing Address

Epilepsy Research Program
Department of Genetic Medicine
Level 9, Rieger Building
Women's and Children's Hospital
72 King William Road
North Adelaide
South Australia 5006

Phone/Fax/Email

Ph (08) 8161 6304

Fax (08) 8161 7342

Email  john.mulley@cywhs.sa.gov.au

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