Prevalence And Characterisation Of FMR1 Gene's Premutation Carriers Amongst Older Males Presenting With Tremor/ataxia
Funder
National Health and Medical Research Council
Funding Amount
$199,450.00
Summary
The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the ....The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the FMR1 specific protein product (FMRP), the pathways from premutation to a neurological disorder are unknown. In this disorder, neurological dysfunction is associated with brain atrophy visible in magnetic resonance (MRI) images. Molecular studies showed increased levels of 'messenger' RNA (mRNA), which indicates overexpression of FMR1 gene . Our own study showed significantly increased (41.7%) prevalence of neurological involvement in male premutation carriers aged >50, compared with age-matched norms. Moreover, a screening of patients with two neurological disorders associated with tremor showed a significant increase of premutation carriers (5%- 22%). The aim of this study is to test hypotheses about the association of late-onset neurological disorders of unknown cause presenting tremor and imbalance, with a fragile X premutation in males, by screening for the presence of this premutation; and then conducting a full assessment of the identified premutation carriers, including detailed neurological, neuropsychological and MRI tests, to establish the spectrum of neurological involvement. This involvement will be correlated with the molecular (DNA, mRNA, FMRP) findings. The results will contribute to understanding the mechanisms of neurological involvement caused by this premutation. Moreover, estimation of the prevalence of this premutation in relevant neurological disorders will impact on standard diagnostic, and possibly future treatment approaches in neurology clinics.Read moreRead less
Double Stranded RNA - The Common Pathogenic Agent In Expanded Repeat Genetically Inherited Neurodegenerative Diseases
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
At least twenty human genetic diseases are due to the expansion of existing repeat sequences beyond a common threshold copy number. While many of these diseases have a common mutation mechanism and share many clinical features the molecular steps critical to their pathogenesis are not yet understood. This project will test the hypothesis that expanded repeat containing RNA, specifically in its double-stranded form, is a common pathogenic agent in many of these diseases.
Interdisciplinary Insights Into The Rational Design Of Malaria Therapy And Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Malaria is a global health concern with almost half a million deaths annually. There is an urgent need for a highly effective malaria vaccine and new antimalarials. However, despite decades of research into this pathogen, our understanding of what causes illness in a person and how immunity operates is limited. This project will use a mathematical modelling approach to provide a new way to understand infection, as a rapidly changing and intricate process.
New High-risk Variants For Colorectal Cancer: The Post-GWAS Era
Funder
National Health and Medical Research Council
Funding Amount
$710,105.00
Summary
Our aim is to discover new genes that greatly increase bowel cancer risk. If we can identify these carriers we may be able to prevent them getting cancer. By studying DNA related to bowel cancer, using a novel family design, we will identify families most likely to carry the new genes. We will focus genetic testing, using new techniques, to look for mutations in these prioritised families. Identified mutations will be tested in a 3,500 bowel cancer cases to see how important they are.
Dominant Repeat Expansion Diseases - A Common RNA Mediated Pathogenic Pathway?
Funder
National Health and Medical Research Council
Funding Amount
$281,118.00
Summary
There are fourteen human genetic diseases that are caused by a similar mutation mechanism and have similar clinical outcomes - the loss of function, degeneration and eventual death of nerve cells. This group of diseases includes Huntington's Disease. They are transmitted from parent to offspring such that each child of an affected parent has 50% risk of inheriting the affected gene and therefore developing the disease. The symptoms of these diseases typically develop later in life - between the ....There are fourteen human genetic diseases that are caused by a similar mutation mechanism and have similar clinical outcomes - the loss of function, degeneration and eventual death of nerve cells. This group of diseases includes Huntington's Disease. They are transmitted from parent to offspring such that each child of an affected parent has 50% risk of inheriting the affected gene and therefore developing the disease. The symptoms of these diseases typically develop later in life - between the ages of 35 and 50 years. While the different genes for these diseases have been identified the pathways that lead from their similar form of mutation to their similar clinical outcomes are not yet understood. Some evidence suggests that certain of these diseases have a common toxic component but this component is not shared by all of the disease genes and so an additional agent that they have in common is being sought. This research will use a genetic model organism - the vinegar fly, Drosophila melanogaster, to test the identity of a good candidate (RNA) for a common toxic agent and to provide information about the pathway by which RNA leads to nerve cell degeneration and death. Accurate and complete knowledge of the identity and composition of the pathways that lead from the mutation to the disease are crucial for correct target identification in the development of drug leads.Read moreRead less
Integrating Immunity And Genetics In Follicular Lymphoma To Establish A Prognostic Score Fit For The Modern Era
Funder
National Health and Medical Research Council
Funding Amount
$1,377,174.00
Summary
Follicular lymphoma (FL) is divided into early and advanced stages. Early stage FL is frequently cured, but there is no way to identify who will be cured and who won't. By contrast advanced stage FL is incurable. Our unique access to well-annotated clinical trial and population based cohorts allows us to perform a detailed biological comparison of early and advanced FL, to gain a deeper understanding of the impediments to eradicating the disease, and to predict outcome to conventional therapy.