Every human is derived from a single cell created at fertilisation. All the information required to create a highly complex, three-dimensional, free-living individual is contained in this cell. How this process occurs is one of the oldest scientific questions. Many birth defects arise following errors in the program that controls how normal three-dimensional shapes are achieved.
The Craniofacial Research team focuses on determining how the patterns and shapes of the craniofacial and limb skeleton are established in the early embryo. The majority of birth defects affecting the face also involve malformation of the limbs, indicating the patterning mechanisms in the two systems work in similar ways. By comparing the genetic pathways at work during development of the craniofacial and limb skeletons in animals, researchers are gaining unique insights into how each system is controlled.
In addition, research into human genetics is enabling the team to identify the genes responsible for birth defects, providing a much deeper understanding of how skeletal development is controlled.
Understanding the causes of birth defects
Birth defects involving the face affect approximately one percent of all babies but the genes involved in most of these conditions are unknown. A genetic approach called ENU mutagenesis allows phenotypes of interest to be identified without any prior knowledge of specific genes involved in the development of the organ system of interest. Once useful phenotypes are established, rapid gene mapping approaches have been developed to identify the mutated gene. The Murdoch Children's Craniofacial researchers have identified the mutated genes in three mouse strains which model the human birth defects known as Jeune syndrome, frontonasal dysplasia and Goldenhar syndrome. Each of these mouse models has major developmental defects in multiple organs. Analysis of the origins of these birth defects will directly contribute to our understanding of what causes these birth defects in humans.
In addition, the team has patient samples from individuals with these conditions and uses data from the mouse models to identify the defect causing genes in humans. This project will provide an opportunity for students to learn developmental biology approaches to understanding human birth defects and gain skills in a wide range of molecular biology techniques. Upon completion of this project, students will be in a strong position to initiate their own research into the genetic and developmental basis of human birth defects.
A novel surveillance system that prevents human birth defects
The signalling networks that regulate patterning and coordinated growth during early embryonic development are essential for the formation of normal, healthy children. Genetic lesions that disturb these networks are responsible for structural birth defects that are common and have an enormous impact on affected individuals and their families. The Craniofacial team researchers have identified a unique surveillance system with a broad role in ensuring the fidelity of embryonic development. Disruption of this system, by over expression of a newly-identified MicroRNA (miRNA) cluster, does not result in specific birth defects, but predisposes embryos to a diverse range of structural anomalies.
Disruption of this system could therefore underpin a wide range of sporadic birth defects in humans. This project will analyse the genes of mice and chicks, but more specifically, the role of the miRNA cluster in the animals’ development. The identification of a surveillance mechanism which monitors the fidelity of tissue and organ formation is completely novel and has profound implications for our understanding of embryonic development and the origins of congenital anomalies.
- Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions. 2017
- Genotype and phenotype spectrum of NRAS germline variants. 2017
- KBG syndrome: An Australian experience. 2017
- Best Practices for the Diagnosis and Evaluation of Infants With Robin Sequence: A Clinical Consensus Report. 2016
- Clinical and Molecular Characterisation of Children with Pierre Robin Sequence and Additional Anomalies. 2016
- Frontonasal Dysplasia: Towards an Understanding of Molecular and Developmental Aetiology. 2016
- GAPTrap: A Simple Expression System for Pluripotent Stem Cells and Their Derivatives. 2016
- Limb patterning genes and heterochronic development of the emu wing bud. 2016
- Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations. 2015
- Olfr603, an orphan olfactory receptor, is expressed in multiple specific embryonic tissues. 2015
- YPEL1 over-expression in early avian craniofacial mesenchyme causes mandibular dysmorphogenesis by up-regulating apoptosis. 2015
- bfb, a Novel ENU-Induced blebs Mutant Resulting from a Missense Mutation in Fras1. 2013
- Cauli: a mouse strain with an ift140 mutation that results in a skeletal ciliopathy modelling jeune syndrome. 2013
- Characterization of a novel ENU-generated myosin VI mutant mouse strain with congenital deafness and vestibular dysfunction. 2013
- Clinical comparison of overlapping deletions of 19p13.3 2013
- Eeyore : a novel mouse model of hereditary deafness 2013
- Etiology and Audiological Outcomes at 3 Years for 364 Children in Australia 2013
- Folic acid supplementation use and the MTHFR C677T polymorphism in orofacial clefts etiology: an individual participant data pooled-analysis 2013
- Genome-wide ENU mutagenesis in combination with high density SNP analysis and exome sequencing provides rapid identification of novel mouse models of developmental disease. 2013
- Prenatal diagnosis of agenesis of the corpus callosum and cerebellar vermian hypoplasia associated with a microdeletion on chromosome 1p32a 2013
- Resting heart rate and physical activity as risk factors for lone atrial fibrillation: a prospective study of 309 540 men and women 2013
- X-Chromosomal Maternal and Fetal SNPs and the Risk of Spontaneous Preterm Delivery in a Danish/Norwegian Genome-Wide Association Study 2013
- Application of a Novel Hybrid Study Design to Explore Gene-Environment Interactions in Orofacial Clefts 2012
- Genetics of Nonsyndromic Orofacial Clefts 2012
- Identification of three novel hearing loss mouse strains with mutations in the Tmc1 gene. 2012
- Inner ear morphology is perturbed in two novel mouse models of recessive deafness. 2012
- Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature 2012
- Rare syndromes of the head and face - Pierre Robin Sequence 2012
- Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1. 2012
- Using offspring-parent triads to study complex traits: A tutorial based on orofacial clefts 2012
- X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia 2012
- A Mutation in Synaptojanin 2 Causes Progressive Hearing Loss in the ENU-Mutagenised Mouse Strain Mozart 2011
- An ENU-Induced Mutation of Cdh23 Causes Congenital Hearing Loss, but No Vestibular Dysfunction, in Mice. 2011
- CXCL14 expression during chick embryonic development. 2011
- Fetal Genetic Risk of Isolated Cleft Lip Only versus Isolated Cleft Lip and Palate: A Subphenotype Analysis using Two Population-Based Studies of Orofacial Clefts in Scandinavia 2011
- Phenotypic Variability of Distal 22q11.2 Copy Number Abnormalities 2011
- Patrick Sexton, Monash Institute of Pharmaceutical Sciences, Parkville, Australia
- Joe Nadeau, Pacific Northwest Diabetes Institute, Seattle, USA
- Marianne Bronner, California Institute of Technology, Pasadena, USA