Professor John Christodoulou

Biography:

John Christodoulou is a medical graduate of the University of Sydney, and has formal qualifications in paediatrics, medical genetics and genetic pathology, with his main current focus of clinical practice being in the diagnosis and management of children with inborn errors of metabolism. He has an active laboratory-based and clinical Rett syndrome research program, as well as in genetic metabolic disorders, including phenylketonuria (PKU) and the mitochondrial respiratory chain (energy production) disorders, and has a strong research interest in the application of next generation sequencing technologies for disease gene discovery in rare Mendelian disorders. He was the Director of the Western Sydney Genetics Program at the Children's Hospital at Westmead, and the Head of the Discipline of Genetic Medicine at Sydney University until December 2015. In January of this year took up the inaugural Chair of Genomic Medicine at the Murdoch Childrens Research Institute and the University of Melbourne.

John is a former President of the Human Genetics Society of Australasia (2005-2007), and served on the NHMRC Principal Committee, the Human Genetics Advisory Committee from 2009 to 2015.

Awards:

1. National Health and Medical Research Council of Australia Postgraduate Medical Research Fellowship -1987-1990.
2. American Society of Human Genetics Postdoctoral Clinical Research Student Award, 1992.
3. Vice-Chancellor's Award for Excellence in Postgraduate Research Higher Degree Supervision, 2004.
4. Became a Member of the Order of Australia (AM), January 2010. Awarded in recognition of my contributions to genetic practice and research, particularly in the area of genetic metabolic disorders.
5. Ippokratis Award for outstanding achievement by a medical professional. Awarded by the Australasian Hellenic Educational Progressive Association (AHEPA), March 2010 .

Research:

Professor Christodoulou has made significant contributions to the field of mitochondrial respiratory chain disorders research include contribution to the discovery of 10 new disease genes, one of which led to the establishment of a specific therapy (riboflavin) as being very effective. In addition, he has delineated and expanded the phenotypes of a number of mitochondrial disorders, and has been involved in the development of a number of new methods, including automation of respiratory chain enzyme analysis, exploration of FACS in the diagnosis of mitochondrial disorders, development of DHPLC for screening mtDNA for mutations, and the use of cybrid technology to delineate the underlying genetic basis of mitochondrial disorders. With collaborators he also identified a naturally occurring dog model of Leigh disease, the genetic basis of which is yet to be established.

Professor Christodoulou has also made significant contributions to the field of RTT research include the development of a highly regarded web-based locus specific MECP2 mutation database, and which has been awarded continuous funding since 2006 from the US-based International Rett Syndrome Foundation. In collaboration with national and international colleagues he has contributed to the careful delineation of the natural history and phenotype-genotype correlations in RTT. Using several RTT mouse models and cell culture approaches using cell lines derived from patients with MECP2 mutations, he has gained further insights into to understanding the pathogenesis of RTT, including ground breaking identification of the first genetic and environmental modifiers of disease severity. His group discovered a new gene, cyclin dependent kinase-like 5 (CDKL5), causing an atypical form of RTT, which has led to a new direction of research into RTT and related disorders. They also identified a novel CDKL5 isoform as the major isoform in brain, necessitating a change in the approach to genetic testing for the CDKL5 disorder.

Projects:

The Biology of Rett Syndrome: MECP2 Mutations and Beyond
The Molecular Pathogenesis of Mitochondrial Respiratory Chain Disorders
Genetically Engineered Probiotics for the Treatment of Human Disease: Phenylketonuria as a Model Disease
Application of Next Generation Sequencing Technologies for Mendelian Gene Disorder Discoveries

1. Kendra J. Bjoraker KJ, Swanson MA, Coughlin CR, Christodoulou J, Tan ES, Fergeson M, Dyack S, Ayesha Ahmad A, Friederich MW, Spector E, Creadon-Swindell G, Hodge MA, Van Hove JLK. Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia. J Pediatr Accepted 8th December 2015
2. Menezes MJ, Guo Y, Zhang J, Riley LG, Cooper ST, Thorburn DR, Li J, Dong D, Li Z, Glessner J, Davis RL, Sue CM, Alexander SI, Arbuckle S, Kirwan P, Keating BJ, Xu X, Hakonarson H, Christodoulou J. Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure, and lactic acidemia. Hum Molec Genet 2015: 24(8); 2297-307.
3. Gold WA, Lacina TA, Cantrill LC, Christodoulou J. MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can be restored using HDAC6 inhibitors. J Mol Med 2015: 93 (1); 63-72
4. Guo Y, Kartawinata M, 2 Li J, Pickett HA, Teo J, Kilo T, M. Barbaro PM, Keating B, Chen Y, Tian L, Al-Odaib A, Reddel RR, Christodoulou J, Xu X, Hakonarson H, Bryan TM. Aplastic Anemia Caused by Mutation of Telomere Protein TPP1. Blood 2014: 124(18); 2767-2774. This paper was the subject of a commentary in the same issue of the journal
5. Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Alodaib A, Abrams AJ, K Sugano, A Yonezawa, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim M, Lin J-P, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, Züchner S, Muntoni F, Houlden H. Treatable Childhood Neuronopathy Caused by Mutations in Riboflavin Transporter RFVT2. Brain 2014: 137(Pt 1); 44-56. (Was the subject of an editorial commentary in the same issue of the Journal: Timmerman C, de Jonghe P. Promising riboflavin treatment for motor neuron disorder. Brain 2014: 137; 44-56.
6. Gaignard, P, Menezes M, Schiff M, Bayot A, Rak M, de Baulny HO, Su C-H, Gillerom M, Lombes A, Abida H, Tzagoloff A, Riley L, Cooper ST, Mina K, Davis MR, Allcock RJN, Kresoje N, Laing NG, Thorburn DR, Slama A, Christodoulou J, Rustin P. Mutations in the cytochrome c1 subunit of respiratory chain complex III cause insulin-responsive hyperglycemia. Am J Hum Genet 2013: 93; 384-389.
7. Fehr S, Wilson, M, Downs, J, Williams S, Murgia A, Sartori, S, Vecchi M, Ho G, Polli R, Psoni S, Bao X, de Klerk N, Leonard H, Christodoulou J. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Human Genet 2013: 21 (3); 266-273.
8. Calvo SE, Compton AG, Hershman SB, Lim S-C, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, DiMauro S, Thorburn DR, Mootha VK. Molecular Diagnosis of Mitochondrial Disorders with Targeted Next-Generation Sequencing. Science Transl Med 2012: 4(118); 118ra10. (featured on the NIH National Human Genome Research Institute's (NHGRI) Genomic Advance of the Month for January. See www.genome.go

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9. Tucker EJ, Hershman SG, Koehrer C, Belcher-Timme CA, Goldberger OA, Christodoulou J, Silberstein J, McKenzie M, Ryan MT, Compton AG, Calvo SE, Rajbhandary UL, Thorburn DR, MoothaVK. Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab. 2011: 14; 428–434
10. Williamson SL, Giudici L, Kilstrup-Nielsen C, Gold W, Pelka GJ, Tam PPL, Grimm A, Prodi D, Landsberger N, Christodoulou J. A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain. Human Genet. 2012: 131(2); 187-200

Funding:

International Rett Syndrome Foundation Database Grant #2242 – 2014 – 2016
RettBASE: IRSF MECP2 Variation Database – a Global Resource
J. Christodoulou (CIA)
United Mitochondrial Diseases Foundation Grant – 2015 – 2016
Utility of FGF21 and GDF15 as Diagnostic and Prognostic Biomarkers of Mitochondrial Respiratory Chain Disorders
J. Christodoulou (CIA)
NHMRC Targeted Research Grant APP1113531 – 2016 – 2020
Preparing Australia for Genomic Medicine – A proposal by the Australian Genomics Health Alliance
J Christodoulou (CI)
NHMRC Project APP1128845 – 2017-2020
Solving the Unsolved: A Functional, Computational and Omics Approach to Identifying the Missing Diagnoses of Patients with Mitochondrial Disease
J Christodoulou – (CIB)
NHMRC CRE APP1117394 – 2016-2021
Transforming the Diagnosis and Management of Severe Neurocognitive Disorders through Genomics
J Christodoulou (CIH)
NHMRC CRE APP1098949 – 2015 – 2020
National Centre of Research Excellence for Mitochondrial Disease – Shifting the diagnostic paradigm to improve health outcomes
J Christodoulou (CIC)
NHMRC APP1124599 – 2016 – 2019
Histone deacetylase 6 inhibition: A novel potential treatment for Rett syndrome, a leading form of sever intellectual disability in females
J Christodoulou (CIA)