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
Risk Factors Associated With The Expansion Of CGG Repeat Sequences In The FMR1 (fragile X) Gene: A Study In Tasmania
Funder
National Health and Medical Research Council
Funding Amount
$246,020.00
Summary
This study will identify the risk factors that lie in an individual's DNA profile for a disease called fragile X syndrome. This disease is the most common form of intellectual disability that runs in families caused by an unusual form of change in a particular gene called FMR1, whereby a very short sequence of DNA in a gene expands by repeating itself to such an extent that once it reaches a certain size the whole gene stops working and the disease occurs. The expansion in the gene is not unifor ....This study will identify the risk factors that lie in an individual's DNA profile for a disease called fragile X syndrome. This disease is the most common form of intellectual disability that runs in families caused by an unusual form of change in a particular gene called FMR1, whereby a very short sequence of DNA in a gene expands by repeating itself to such an extent that once it reaches a certain size the whole gene stops working and the disease occurs. The expansion in the gene is not uniform across the generations, and only occurs when passed on from the mother to her offspring. However, many females carrying only a short sequence may pass on, for unknown reasons, either a large expanded sequence leading to disease, or one similar in size to her own. This complexity in the progression of the number of CGG repeats means that there is a relatively large number of mothers, ~1 in 300, who are quite normal but at risk of having an affected offspring. The factors that trigger this expansion in the DNA are presently not well understood, but a number of genetic markers in the FMR1 gene have been implicated. This study will assess the contribution of an array of these genetic markers in determining the risk of expansion of the short repeat from mother to offspring and hence the risk of fragile X. Conducting this study in Tasmania has two advantages. First, by having access to genealogical records that permit the linking of fragile X families we shall be able to identify common predisposing factors of fragile X more accurately. Second, by testing the whole population with intellectual disability in one State of manageable size we shall obtain an unbiased estimate of the prevalence of fragile X.Read moreRead less
Exploiting Sexual Differences In Germline Biology To Resolve The Causes Of Germline Mutation
Funder
National Health and Medical Research Council
Funding Amount
$315,914.00
Summary
Mutagenesis during the production of sex cells is a fundamental biological process and the cause of inherited human disorders. These disorders span the entire spectrum of diseases that have a genetic component, such as autoimmune diseases and cancers, therefore influencing all age groups. A better understanding of the mechanisms underlying this process is a priority since it is the essential knowledge required for understanding all of the factors that contribute to this array of debilitating dis ....Mutagenesis during the production of sex cells is a fundamental biological process and the cause of inherited human disorders. These disorders span the entire spectrum of diseases that have a genetic component, such as autoimmune diseases and cancers, therefore influencing all age groups. A better understanding of the mechanisms underlying this process is a priority since it is the essential knowledge required for understanding all of the factors that contribute to this array of debilitating diseases, and for devising effective preventative and diagnostic measures. To attain this understanding necessitates establishing the mechanistic origins of germline mutagenesis. Two basic approaches are employed to understand this process. The first assesses the incidence of mutation in pedigrees. This identifies the spectrum of risk mutations underlying the specific disease surveyed. Because other biological processes also influence these observations, the results from this approach do not reflect the underlying germline mutation spectra and are therefore not translatable between diseases. As mutations are rare events, it is prohibitive to obtain sufficient observations to resolve the underlying mechanisms. The second approach employs comparative genomic data, and uses differences in germline biology to estimate sex-biased effects. This comparative approach benefits from the accumulation of mutations over vast periods of time. The approach has not, however, been applied to diagnose the mechanistic origins of mutations. In this project, we will apply the enormous volume of comparative sequencing data to relate components of the mutagenic spectrum with sexual differences in germline biology. The project will differentiate between different types of mutations, and their association with specific processes will be established. The results will be a determination of the relative contributions of different mechanisms of mutation to germline mutagenesis.Read moreRead less
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
Statistical Methods For Identifying Structural Variation In Tumour Genomes Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$243,458.00
Summary
New DNA sequencing technology can sequence a tumour genome affordably in 2 weeks. This re-sequencing data can be used to find small mutations and large-scale chromosomal rearrangements that together are the drivers of cancer. These may one day be used to guide cancer therapy. This project will develop new algorithms for finding mutations and apply these to discover the genetic basis of drug resistance in a model lymphoma system.
Investigating The Pathogenic Mechanism Of Mutations In IQSEC2 Causing Non-syndromic Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$449,016.00
Summary
Intellectual disability is frequent in the population, as many as 1 in every 50 people in the world affected. Mutations in IQSEC2, an X-chromosome gene, cause intellectual disability. We will screen 1000 families with this disability for mutations in IQSEC2, building the picture of disease symptoms, contributing to informed genetic counselling. We will investigate functional impacts of these mutations in neuronal cultures, increasing our understanding of the causes of intellectual disability.
Understanding Influenza Mortality And The Effects Of Vaccination In The Elderly
Funder
National Health and Medical Research Council
Funding Amount
$446,877.00
Summary
We will analyse mortality from influenza and other causes to estimate the numbers of deaths from other causes that are triggered by influenza in elderly persons, and to test the value of vaccination in preventing those deaths. Our results will help to decide whether an expensive clinical trial is really needed to show the benefit of influenza vaccination on all-cause mortality in the elderly.