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.
Molecular Mechanisms Of Disease In The Collagen VI-related Muscular Dystrophies
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
The inherited muscular dystrophies are an important cause of disability in Australia. This project concentrates on the second most common group of congenital muscular dystrophies - those caused by mutations in collagen VI and its interacting partners. We will determine how mutations affect the structure of the protein and how the muscle is disrupted by the mutations. This work will open the way for research into potential therapies. We will also find new genes that cause muscular dystrophy.
Identification Of New Mutations That Contribute To Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$323,825.00
Summary
Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the genetic defects that contribute to disease initiation and progression. Although a number of breast cancer susceptibility genes have been identified, the contribution each of these genes makes to breast cancer susceptibility is currently unclear. This is partly due to limitations in current diagno ....Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the genetic defects that contribute to disease initiation and progression. Although a number of breast cancer susceptibility genes have been identified, the contribution each of these genes makes to breast cancer susceptibility is currently unclear. This is partly due to limitations in current diagnostic processes and an incomplete understanding of all of the genetic elements for which disruption can lead to loss of gene function. This proposal aims to identify regulatory pathways that are critical for the expression of an important breast cancer gene called BRCA1. Furthermore, it aims to determine the status of these pathways in breast cancer patients, thus expanding our knowledge of the actual contribution that disruption of this gene makes to this disease. It also aims to determine the potential for trans-acting factors to regulate the expression of BRCA1 and thus activity of the BRCA1 pathway. The predicted outcome of this research is an improved ability to perform presymptomatic diagnostic testing for breast cancer and the ultimately the development of more effective drugs to treat certain breast tumours.Read moreRead less
Characterisation Of Novel Cilia Proteins And Roles In Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$339,410.00
Summary
Cilia and flagella are tiny hair-like structures attached to the surface of most cells in the body. They perform different roles in many different organs including the brain and play key roles in our sensory systems. This project aims to identify and characterise components of cilia in order to better understand the causes of disorders where the cilia do not function properly.
PArkin Co-Regulated Gene (PACRG), Parkin And Parkinsonism.
Funder
National Health and Medical Research Council
Funding Amount
$397,740.00
Summary
Parkinson's disease (PD) is a common neurodegenerative disorder affecting greater than two percent of individuals over the age of 65. The disease is characterised by tremor, slowness of movement, rigidity and postural instability. Current treatment regimes may provide some measure of symptomatic relief, but currently there is no treatment to halt or slow the progression of this debilitating disease. PD currently affects an estimated 35,000 people in Australia and this figure is predicted to incr ....Parkinson's disease (PD) is a common neurodegenerative disorder affecting greater than two percent of individuals over the age of 65. The disease is characterised by tremor, slowness of movement, rigidity and postural instability. Current treatment regimes may provide some measure of symptomatic relief, but currently there is no treatment to halt or slow the progression of this debilitating disease. PD currently affects an estimated 35,000 people in Australia and this figure is predicted to increase significantly as the population ages. PD is a complex disorder, the causes and disease mechanisms are not well understood. However, in the past 10 years several genes have been identified that can cause PD when disrupted. We have identified a new gene that we believe may be involved in PD. The overall aim of this proposal is to characterise this gene and what role it plays in the development of PD. Understanding the expression and function of this gene may significantly advance our understanding of this disorder. Using these results, we aim to model Parkinson's disease in cellular and animal systems; these may provide powerful insight into the molecular pathway(s) perturbed in PD and a means to develop novel therapeutic approaches to alleviate or prevent the disorder.Read moreRead less
Identification Of Genetic Defects In Muscle Contractile Proteins
Funder
National Health and Medical Research Council
Funding Amount
$167,167.00
Summary
Congenital myopathies are a group of mostly inherited disorders which cause muscle weakness from birth. Some congenital myopathies can lead to the early death of the affected child, while other types are compatible with reaching adulthood. Like any diseases of childhood, the congenital myopathies cause great trauma to the families with an affected child. Couples at risk of having another affected child often opt to wait for prenatal diagnosis to become available for their particular disease befo ....Congenital myopathies are a group of mostly inherited disorders which cause muscle weakness from birth. Some congenital myopathies can lead to the early death of the affected child, while other types are compatible with reaching adulthood. Like any diseases of childhood, the congenital myopathies cause great trauma to the families with an affected child. Couples at risk of having another affected child often opt to wait for prenatal diagnosis to become available for their particular disease before attempting to have further children. However, prenatal diagnosis is only possible once the gene causing a disorder and the mutation in an individual family are identified. Identifying the disease-causing mutation may help the common feelings of guilt in the parents if it can be shown that the affected child has a new mutation, and there is nothing the parents could have done to stop their child having the disease. In the past, this Laboratory, the Molecular Neurogenetics Laboratory at the Australian Neuromuscular Research Institute, amongst others, has identified disease genes for the congenital myopathies. Prenatal diagnosis is now possible for those families whose disease-causing mutation has been identified. However the genetic cause of most of the congenital myopathies remains unknown. This Laboratory has become a reference centre for genetic studies of the congenital myopathies, especially the major form called nemaline myopathy. DNA samples have been sent here from around the world for study. This project aims to study this DNA, to identify other disease genes causing the congenital myopathies in order to help the families at risk with these conditions who currently cannot have prenatal diagnosis. Finding the genes also increases understanding of the diseases. It clarifies which proteins are involved. It allows studies of the mutated proteins to be undertaken. It makes it possible to understand how the diseases arise allowing future treatment of the conditions.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
We propose to use a number of genetic approaches to identify key mutations involved in Polycythemia vera. We will analyse patient material, use cell lines and mouse models to investigate any new mutations. We also aim to dissect the role of an important blood cell surface receptor and its cooperation with the mutation in JAK2 recently shown to be important in this disease. These approaches will lead to better understanding of the disease and potential new diagnostic and drug strategies.
Psychosocial Predictors Of Developing Breast Cancer In Women From High Risk Breast Cancer Families
Funder
National Health and Medical Research Council
Funding Amount
$593,875.00
Summary
Over the past 20 years, studies have highlighted the possible roles of stressful life events and distress, possibly mediated by social support and personality, in causing or speeding up the development of breast cancer. This possibility is of strong concern to consumers. To date, there have been few well designed, prospective studies of this issue. Furthermore, no previous studies have specifically targeted women at increased risk because of their family history. Over the past 7 years, it has be ....Over the past 20 years, studies have highlighted the possible roles of stressful life events and distress, possibly mediated by social support and personality, in causing or speeding up the development of breast cancer. This possibility is of strong concern to consumers. To date, there have been few well designed, prospective studies of this issue. Furthermore, no previous studies have specifically targeted women at increased risk because of their family history. Over the past 7 years, it has become possible to identify 2 breast cancer genes (BRCA1 and BRCA2). Female carriers of mutations in these genes with a strong family history have an estimated lifetime risk of between 35% and 85%. The Kathleen Cuningham Consortium for Research into Familial Breast Cancer (KConFab) was established 7 years ago to coordinate the collection of genetic, epidemiological and clinical data in Australian families with a dominantly inherited predisposition to breast cancer. Due to the high rate of breast cancer diagnoses in this group, and the systematic recruitment of large numbers of high risk women by KConFab, there is a unique and temporary opportunity to conduct a rigorous study to resolve this question, with sufficient numbers involved. The study is a world first, and will provide the best data to date in this area. If the study demonstrates a relationship between psychosocial factors and the development of breast cancer in women from high risk breast cancer families, subsequent identification of vulnerable individuals and the implementation of appropriate interventions may have a real impact on reducing morbidity and mortality in this population. Furthermore, the results may have implications for all women in reducing breast cancer incidence.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.