A/Professor Paul Lockhart

Biography:

Associate Professor Paul Lockhart is the Group Leader of Neurogenetic Research at the Murdoch Childrens Research Institute.

He is currently the National Health and Medical Research Council (NHMRC) Career Development Fellow and leads a research group that investigates the molecular basis of neurogenetic disorders.

Paul received his PhD in Genetics (Title: Molecular analysis of copper transport in sheep) from the University of Melbourne in 2000. He was awarded a NHMRC CJ Martin Fellowship to study the genetics of neurodegenerative disorders, specifically Parkinson's disease, with Professor John Hardy (2000-2001) and Professor Matthew Farrer (2002-2003) at The Mayo Clinic, Florida. He returned to Australia in 2004 and joined the newly formed Bruce Lefroy Centre (BLC) at Murdoch Childrens, with the aim of establishing a laboratory research group to complement the clinical and public health research activities of the BLC. He received a NHMRC RD Wright Fellowship in 2005 and was appointed Co-Director of the BLC in 2009.

Other Affiliations:

Co-Director, Department of Genetics, Bruce Lefroy Centre
Associate Professor, Department of Paediatrics, University of Melbourne

Awards:

Career Development Award (II), NHMRC, 2012-2015
Early Career Prize, International Skeletal Dysplasia Society, 2010
AW Campbell Award, Australian Neuroscience Society, 2008
Rising Star, MCRI, 2007
RD Wright Fellow, NHMRC, 2005-2009

Research:

The identification and characterisation of genes underlying Mendelian disorders has been responsible for the rapid advances in our understanding of human disease over the last 20 years, and has considerable impact on our understanding of complex common diseases that are currently considered to be idiopathic.

Recent advances in genetic technologies mean we now have the ability to sequence entire exomes and genomes in a rapid and cost effective manner. This means gene discovery can now be effectively performed in families with few affected individuals and sib-pairs, both previously underpowered for such analysis. Indeed, we are rapidly approaching the point where whole exome/genome sequencing of individuals will be a cost-effective method for diagnosis of many disorders. These genome sequence datasets have enormous potential for application in the rapidly developing field of personalised medicine. These advances have particular relevance to disorders of the brain, which is a specific area of research interest.

In Australia, brain and mind disorders collectively are one of the largest and fastest growing disease burdens. Affecting both the young and the elderly, these disorders are typically chronic and debilitating with a large economic cost to individuals and the community. A current focus of the laboratory is to apply new genomic technologies and capacity to neurogenetic disorders that have previously proven intractable to genetic analysis. The laboratory works very closely with the clinical services of Genetic Health Services Victoria and the Royal Children's Hospital. Once novel disease-associated genes are identified, we perform molecular studies in cell and animal models to determine the function of the encoded protein and investigate the underlying pathogenesis of disease. In addition to the immediate counselling and clinical benefit to affected patients and families, this research is essential for the development of treatment programs and prevention or onset-delay strategies for brain and mind disorders.

Projects:

1. Accelerated Gene Identification Program (AGIP)
2. Understanding the molecular basis of Parkinson’s disease
3. Clinical and Molecular Genetic Study of Autism Spectrum Disorders
4. Understanding the cause of brain malformations.

Tankard RM, Bennett MF, Degorski P, Delatycki MB,Lockhart PJ*, Bahlo M*. Detecting tandem repeat expansions in cohorts sequenced with short-read sequencing data. Am J Hum Genet. 2018 Nov 20. pii: S0002-9297(18)30367-7. doi: 10.1016/j.ajhg.2018.10.015. [Epub ahead of print].

Gao, Y., G.R. Wilson, S.E.M. Stephenson, K. Bozaoglu, M.J. Farrer, and P.J. Lockhart*, The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease. Mov Disord (2018) 33: 196-207.

Stessman, H.A et al, I.E. Scheffer, M.B. Delatycki, P.J. Lockhart, F. Hormozdiari, B. Harich, A. Castells-Nobau, K. Xia, H. Peeters, M. Nordenskjold, A. Schenck, R.A. Bernier, and E.E. Eichler, Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet (2017) 49: 515-26.

Marsh, A.P., D. Heron, T.J. Edwards, A. Quartier, C. Galea, C. Nava, A. Rastetter, M.L. Moutard, V. Anderson, P. Bitoun, J. Bunt, A. Faudet, C. Garel, G. Gillies, I. Gobius, J. Guegan, S. Heide, B. Keren, F. Lesne, V. Lukic, S.A. Mandelstam, G. McGillivray, A. McIlroy, A. Meneret, C. Mignot, L.R. Morcom, S. Odent, A. Paolino, K. Pope, F. Riant, G.A. Robinson, M. Spencer-Smith, M. Srour, S.E. Stephenson, R. Tankard, O. Trouillard, Q. Welniarz, A. Wood, A. Brice, G. Rouleau, T. Attie-Bitach, M.B. Delatycki, J.L. Mandel, D.J. Amor, E. Roze, A. Piton, M. Bahlo, T. Billette de Villemeur, E.H. Sherr, R.J. Leventer, L.J. Richards*, P.J. Lockhart*, and C. Depienne*, Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nat Genet (2017) 49: 511-4.

Sim, J.C., T. Scerri, M. Fanjul-Fernandez, J.R. Riseley, G. Gillies, K. Pope, H. van Roozendaal, J.I. Heng, S.A. Mandelstam, G. McGillivray, D. MacGregor, L. Kannan, W. Maixner, A.S. Harvey, D.J. Amor, M.B. Delatycki, P.B. Crino, M. Bahlo, P.J. Lockhart*, and R.J. Leventer*, Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol (2016) 79: 132-7.

Phelan, D.G., D.J. Anderson, S.E. Howden, R.C. Wong, P.F. Hickey, K. Pope, G.R. Wilson, A. Pebay, A.M. Davis, S. Petrou, A.G. Elefanty, E.G. Stanley, P.A. James, I. Macciocca, M. Bahlo, M.M. Cheung, D.J. Amor, D.A. Elliott, and P.J. Lockhart*, ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. Eur Heart J (2016) 37: 2586-90.

Leventer, R.J., T. Scerri, A.P. Marsh, K. Pope, G. Gillies, W. Maixner, D. MacGregor, A.S. Harvey, M.B. Delatycki, D.J. Amor, P. Crino, M. Bahlo, and P.J. Lockhart*, Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR. Neurology (2015) 84: 2029-32.

Lessel, D., B. * Vaz, S. * Halder*, P.J. Lockhart*, I. Marinovic-Terzic*, J. Lopez-Mosqueda, M. Philipp, J.C. Sim, K.R. Smith, J. Oehler, E. Cabrera, R. Freire, K. Pope, A. Nahid, F. Norris, R.J. Leventer, M.B. Delatycki, G. Barbi, S. von Ameln, J. Hogel, M. Degoricija, R. Fertig, M.D. Burkhalter, K. Hofmann, H. Thiele, J. Altmuller, G. Nurnberg, P. Nurnberg, M. Bahlo, G.M. Martin, C.M. Aalfs, J. Oshima, J. Terzic, D.J. Amor, I. Dikic, K. Ramadan, and C. Kubisch, Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet (2014) 46: 1239-44.

Coe, B.P., K. Witherspoon, J.A. Rosenfeld, B.W. van Bon, A.T. Vulto-van Silfhout, P. Bosco, K.L. Friend, C. Baker, S. Buono, L.E. Vissers, J.H. Schuurs-Hoeijmakers, A. Hoischen, R. Pfundt, N. Krumm, G.L. Carvill, D. Li, D. Amaral, N. Brown, P.J. Lockhart, I.E. Scheffer, A. Alberti, M. Shaw, R. Pettinato, R. Tervo, N. de Leeuw, M.R. Reijnders, B.S. Torchia, H. Peeters, E. Thompson, B.J. O'Roak, M. Fichera, J.Y. Hehir-Kwa, J. Shendure, H.C. Mefford, E. Haan, J. Gecz, B.B. de Vries, C. Romano, and E.E. Eichler, Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet (2014) 46: 1063-71.

Mill, P*., P.J. Lockhart*, E. Fitzpatrick, H.S. Mountford, E.A. Hall, M.A. Reijns, M. Keighren, M. Bahlo, C.J. Bromhead, P. Budd, S. Aftimos, M.B. Delatycki, R. Savarirayan, I.J. Jackson, and D.J. Amor, Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am J Hum Genet (2011) 88: 508-15.

Wilson, G.R., H.X. Wang, G.F. Egan, P.J. Robinson, M.B. Delatycki, M.K. O'Bryan, and P.J. Lockhart*, Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse. Hum Mol Genet (2010) 19: 1593-602.

Funding:

NHMRC Project grant 1161549, 2019-2021, Understanding the molecular basis of disorders of cortical development to inform diagnosis and management (CIs: Lockhart, Leventer, Robertson, Harvey)

NHMRC Project grant 1144724, 2018-2020, Understanding RAB39B-mediated Parkinson's disease (CIs: Lockhart, Finkelstein, Dottori, Delatycki, Farrer)

NHMRC Project grant 1128933, 2017-2018, Tuberous sclerosis and epilepsy: using resected tissue to understand pathogenesis and inform management (CIs: Leventer, Lockhart, Harvey)

NHMRC Project grant 1098255, 2016-2020, Understanding the Neurobiology of Autism Spectrum Disorder (CIs: Scheffer, Lockhart, Delatycki, Wilson, Fanjul, Stanley)

NHMRC Project grant 1102207, 2016-2018, A randomised placebo-controlled crossover trial of micronised resveratrol as a treatment for Friedreich ataxia (CIs: Delatycki, Yiu, Corben, Cranswick, Lockhart, Wilmot, Lamont, O'Sullivan)

NHMRC Project grant 1059666, 2014-2016, Determining the genetic control of Corpus Callosum development (CIs: Lockhart, Leventer, Amor, Delatycki)

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