Significance Of Low-level Mosaicism To Intellectual Disability In Paediatric Disorders
Funder
National Health and Medical Research Council
Funding Amount
$483,402.00
Summary
My vision for the next 4 years is to improve outcomes for children and their families with inherited disorders associated with intellectual disability (ID) and autism through earlier diagnosis and intervention. This is of great importance with annual costs of ID close $14.72 billion to the Australian health system, and missed or delayed diagnoses being a significant problem, as ID is found in 1.7% of births, where a specific cause is currently identified in less than half.
Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably e ....Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.Read moreRead less
Determining Fundamental Mechanisms Compromised In Kir-linked Disease States
Funder
National Health and Medical Research Council
Funding Amount
$600,040.00
Summary
The human nervous system and organs are reliant on precisely controlled transmission of electrical currents through sodium and potassium channels. Their core functions are compromised when currents fail to switch on and off normally. Faulty potassium channels are implicated in diabetes, epilepsy and heart failure. This project re-examines the mechanisms controlling potassium channels, with a view to scientific and therapeutic discrimination between the different classes present in human cells.
Novel Fragile X Syndrome Prevalence Estimates In 100,000 Australian Newborns, Prognostic And Health-economic Outcomes: A Retrospective Newborn Screening Study
Funder
National Health and Medical Research Council
Funding Amount
$769,866.00
Summary
Fragile X syndrome (FXS) is a common heritable cause of intellectual disability and co-morbid autism, caused by epigenetic silencing of the FMR1 gene. This will be the world’s largest FXS mutation prevalence study conducted in 100,000 newborns using a novel test targeting epigenetic changes, and will also explore the prognostic outcomes, costs and benefits associated with FXS newborn screening, providing conclusions regarding expanding the current newborn screening in Australia to include FXS.
Identification And Characterisation Of Novel Genes For Congenital Cataract
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Cataracts are the leading cause of blindness worldwide. The term describes a clouding of the lens which may lead to visual impairment. Congenital cataracts (present at birth) are less common than age-related cataract but the lifelong impact on vision can be severe, with a third of patients remaining legally blind. Late complications such as aphakic glaucoma may be blinding. We have shown that congenital cataracts are often inherited and have performed a population-based study in South-Eastern Au ....Cataracts are the leading cause of blindness worldwide. The term describes a clouding of the lens which may lead to visual impairment. Congenital cataracts (present at birth) are less common than age-related cataract but the lifelong impact on vision can be severe, with a third of patients remaining legally blind. Late complications such as aphakic glaucoma may be blinding. We have shown that congenital cataracts are often inherited and have performed a population-based study in South-Eastern Australia over the past 5 years to determine the causative genes. A large number of families have been involved in the study and solid progress has been made in identifying mutations in cataract genes and understanding what effect these may have on the patient's prognosis. We have recently identified a new gene in a large Australian family with a syndrome of cataract, mental retardation and teeth problems. This syndrome, known as Nance-Horan syndrome was originally described in Australia 30 years ago and we have worked with the original family to find the exact gene responsible. We already know that this gene causes the same syndrome in other families and in this project we will examine whether it can cause cataract without the other features or mental retardation without cataract. We will perform a series of experiments to learn what this gene does and how it causes the disease. We have also selected 3 other very interesting families with congenital cataracts for further study as we either know already or strongly suspect that they will enable us to identify further new genes for cataract, and in one case mental retardation. Our work in other diseases indicates that understanding the genes in severe young onset cases can give valuable clues to the causes of age-related forms and may in the future enable new ways to prevent and treat the commonest cause of worldwide blindness.Read moreRead less
Implementation Of A New, Inexpensive And High-throughput Matrix Assisted Laser Desorption / Ionization _ Time Of Flight Mass Spectrometry Test For Superior Detection Of Fragile X Syndrome In Targeted Diagnostics And Newborn Population Screening.
Funder
National Health and Medical Research Council
Funding Amount
$254,175.00
Summary
Background: The Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability. There are now a number of treatments for FXS. However, often this disorder is not clearly recognized. We have developed a novel FXS test that could resolve this issue. Our objective is to develop a commercial package that describes suitability of our test for diagnostic use. If successful this could potentially leading to improvement in the prognosis for FXS children through early treatment int ....Background: The Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability. There are now a number of treatments for FXS. However, often this disorder is not clearly recognized. We have developed a novel FXS test that could resolve this issue. Our objective is to develop a commercial package that describes suitability of our test for diagnostic use. If successful this could potentially leading to improvement in the prognosis for FXS children through early treatment intervention.Read moreRead less
Characterization Of A Novel Epigenetic Boundary And Long Range Epigenetic Modifications Specific To FMR1 Expansion Carriers With Behavioural And Cognitive Disorders - Implications For Earlier Diagnosis And Treatment.
Funder
National Health and Medical Research Council
Funding Amount
$670,836.00
Summary
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and autism and is caused by a faulty switch in the gene FMR1. We have discovered new DNA regions important in FXS. The project aims to explain how these new regions regulate the FMR1 gene. This is essential for the discovery and validation of new avenues for earlier diagnosis, treatments and therapies for children and adults with FMR1 disorders and also for informing reproductive decisions.
Respiratory failure at birth is a major cause of death and disease in newborn infants. At birth the airways must be cleared of liquid to allow the inhalation of air, but, little is known about the process of lung aeration, because it has not been possible to observe or measure it. We have developed imaging and analytical techniques to observed and measure lung aeration. We will determine ventilation procedures that promote uniform lung aeration and minimise lung injury in ventilated infants.
Synchrotron X-ray Assessment Of Airway Surface Physiology For Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$778,228.00
Summary
We seek a cure or long-lasting therapy for the fatal airway disease in cystic fibrosis. Disease is caused by a shallow and dehydrated airway surface liquid (ASL), allowing bacteria to infect the lung. We can introduce a corrective gene into mouse airways where it can be effective for over 1 yr, but no fast, accurate and non-invasive measurement exists to test if treatments are successful. We will develop methods using synchrotron light to directly measure ASL depth changes in live mouse airways.