BMC Seminar - Causative Genetic Mutations in Human Neurodevelopmental Disorders

BMC Semniar Thursday 3 October, 12:00 in Læknagarður Vatnsmýrarvegur 16, room 343

Speaker: Dr. Julian Heng, PhD, Associate Professor of Neuroscience, Curtin Health Innovation Research Institute, Bentley, Australia.

Title: Causative Genetic Mutations in Human Neurodevelopmental Disorders - Detection as a First Step on the Path to New Treatment Options

Abstract: The development of the human brain involves the timely production of neurons, their proper assembly as functional circuits, as well as their appropriate signal integration with cellular counterparts. Abnormal neural circuit formation during fetal development underlies diagnostic traits in neurodevelopmental disorders, such as Malformations of Cortical Development (MCDs). The genetic basis for MCDs is complex, with such diagnoses frequently associated with epilepsy, autism, intellectual disability and cerebral palsy. Also, the molecular mechanisms that underlie these conditions remains to be better understood.

In this presentation, I will discuss our recent findings and unpublished work in our efforts to establish the genetic basis for human neurodevelopmental disorders associated with MCDs. We have integrated high-throughput sequencing data with functional assays to discover novel causative mutations. This has led to the identification of new molecular players that influence neuronal migration, an essential first-step undertaken by newborn neurons in order to assemble as functional circuits in the brain. Our work helps end the diagnostic journey for families living with a neurodevelopmental disorder, improves genetic counselling, and supports personalised care of individuals with early onset brain conditions.

Bio: Julian attained his Bachelor’s of Science with First Class Honours from UWA (1993-1996) then attained his PhD in developmental neuroscience at The University of Melbourne (1998-2002), working at the Howard Florey Institute. Next, he investigated the fundamental mechanisms for neural circuit formation as a CJ Martin Fellow (2004-2006) and then as an MRC UK Career Development Fellow (2006-2008) at the National Institute for Medical Research (UK). In 2010, Julian was appointed Group Leader at the Australian Regenerative Medicine Institute (Clayton, Australia) and received a Career Development Award (Level 1, NH&MRC) to study the genetic mechanisms of brain development and disorder. In 2014, he relocated his research to the Harry Perkins Institute of Medical Research (Perth, Western Australia) to establish the Brain Growth and Disease Laboratory in order to translate his findings into improved genetic diagnostic tests for childhood brain disorder. In 2017, Julian joined Curtin University in March 2017 to relocate his research to the Sarich Neuroscience Research Institute with the goal to apply functional genomics to diagnose and treat early onset neurodevelopmental disorders. His research papers have been cited >2000 times (google scholar) and is published in journals including Nature, Neuron, Nature Cell Biology, Cell Reports and Human Molecular Genetics.

Recent Publications: Hemming, IA, Clement, O, Gladwyn-Ng, I, et al and Agostino, M and Heng, JI. Disease-associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex. Human Mutation. 2019 May 21. doi: 10.1002/humu.23803

Poulton C, et al. and Heng JI. A review of structural brain abnormalities in Pallister-Killian syndrome. Mol Genet Genomic Med. 2018 Jan;6(1):92-98. doi: 10.1002/mgg3.351.

Edvardson S, Tian G, Cullen H, Vanyai H, Ngo L, Bhat S, Aran A, Daana M, Da'amseh N, Abu-Libdeh B, Cowan NJ*, Heng JI*, Elpeleg O*. Infantile Neurodegenerative Disorder Associated with Mutations in TBCD, an Essential Gene in the Tubulin Heterodimer Assembly Pathway. Hum Mol Genet. 2016. Nov 1;25(21):4635-4648. doi: 10.1093/hmg/ddw292 (*co-corresponding authors)

Haas MA, et al. and Heng JI. De novo mutations in DENR disrupt neuronal development and link congenital neurological disorders to defective mRNA translation re-initiation. Cell Reports. 2016, Jun 7;15(10):2251-65. doi: 10.1016/j.celrep.2016.04.090.

Significant publications over career:

Ngo L, Haas M, Qu Z, Li SS, Zenker J, Teng KS-L, Gunnersen JM, Breuss M, Habgood M, Keays DA, Heng JI*. TUBB5 and its disease-associated mutations influence the terminal differentiation and dendritic spine densities of cerebral cortical neurons. Human Molecular Genetics. 2014 Oct 1;23(19):5147-58. doi: 10.1093/hmg/ddu238. (*denotes corresponding author)

Heng JI*, Breuss M*, Poirier K, Tian GL, Jaglin JH, Qu Z, Braun A, Gstrein T, Ngo L, Haas M, Bahi-Buisson N, Moutard M-L, Passemard S, Verloes A, Gressens P, Xie YL, Robson KJH, Rani DS, Thangaraj K, Clausen T, Chelly J, Cowan NJ, Keays DA. Mutations in the gamma-tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities. Cell Reports. 2012 Dec -62. (*denotes equal authorship)

Heng JI, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, Skowronska-Krawczyk D, Bedogni F, Matter JM, Hevner R, Guillemot F. (2008) Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature, 455(7209):114-8.