Molecular Genetic Characterisation Of A Novel X-linked Skeletal Myopathy
Funder
National Health and Medical Research Council
Funding Amount
$158,104.00
Summary
This project aims to identify the genetic basis of a new disease that is characterised by episodes of muscular weakness. This disease only affects males. The signficance of the project is that this is the first description of such a disorder and gives us an opportunity to study a previously unsuspected aspect of human muscle function.
Copy Number Analysis Of Patients With Gonadal Abnormalities Using High Density Microarrays And MLPA
Funder
National Health and Medical Research Council
Funding Amount
$311,187.00
Summary
Congenital conditions in which development of the gonads or anatomical sex is abnormal are surprisingly common. The underlying cause of these problems is most often the failure of genes responsible for proper development of testes or ovaries. Only a small proportion of patients can be explained by mutations in known gonad determining genes. We will analyse DNA from these patients on very high density microarrays to identify new genes that cause abnormalities in testis and ovary development.
Genetic Analysis Of Type 2 Diabetes In Indigenous Australian Pedigrees.
Funder
National Health and Medical Research Council
Funding Amount
$502,500.00
Summary
Type 2 diabetes is a major world health problem. With 300 million people expected to be affected worldwide by 2025 it is a major economic burden. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 7% of the general Australian population have type 2 diabetes, whilst up to 30% of the population in some indigenous communities are affected by this condition. Very few Australians have not been touched in some way by the shadow of diabetes. The precise cau ....Type 2 diabetes is a major world health problem. With 300 million people expected to be affected worldwide by 2025 it is a major economic burden. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 7% of the general Australian population have type 2 diabetes, whilst up to 30% of the population in some indigenous communities are affected by this condition. Very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that inherited tendency is important. This research program will find genes which cause diabetes by searching for them in indigenous Australian pedigrees in which many of the family members are affected by diabetes. Finding the genes which cause diabetes will have significant impact in at least three major ways. Firstly, it will increase our understanding of the disease process. Secondly, it will be possible to develop tests to identify people at risk of diabetes at a very early stage so that therapy can be introduced and complications averted. Thirdly, it will be possible to develop new and more effective approaches for the prevention and treatment of type 2 diabetes.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
Novel Statistical Methods For Genetic Epidemiology
Funder
National Health and Medical Research Council
Funding Amount
$481,505.00
Summary
We are in the midst of a genomics revolution that is transforming epidemiology, medicine and drug discovery. However, the scarcity of sophisticated statistical techniques to deal with the complicated problems inherent in genetic investigations of complex diseases is currently the critical factor limiting the success of human gene discovery programs. Statistical genetic methodology is currently one of the fastest developing areas of epidemiology. In information-intensive' areas such as genetic ep ....We are in the midst of a genomics revolution that is transforming epidemiology, medicine and drug discovery. However, the scarcity of sophisticated statistical techniques to deal with the complicated problems inherent in genetic investigations of complex diseases is currently the critical factor limiting the success of human gene discovery programs. Statistical genetic methodology is currently one of the fastest developing areas of epidemiology. In information-intensive' areas such as genetic epidemiology, genomics, and proteomics, there is a high demand for data analysis and statistical skills. WA has some world class expertise in statistical science, both in academia and in industry. However, this expertise has not yet been applied in a system way to genetic data analysis. We propose to undertake advanced methodological research in statistical genetics and bioinformatics, to produce easy-to-use and accessible software tools and resources that allow methodological advances to be accessed by the Australian research community, and to apply our new methods and tools both to specific disease research and to the developing human genome epidemiology (HuGE) enterprise in WA. These new initiatives in methodological research will draw together a number of currently separate research strands and will provide new tools and resources that will allow applied Australian programs to improve the efficiency of their research into the causes of important. Methodological development in both bioinformatics and statistical genetics are recognized international areas of need.Read moreRead less
STK9, A Second Rett Syndrome Gene: Genetic And Functional Studies
Funder
National Health and Medical Research Council
Funding Amount
$468,750.00
Summary
Rett syndrome (RTT) is a devastating progressive disorder affecting motor and intellectual development. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girls, with an estimated prevalence in Australia of 1 ....Rett syndrome (RTT) is a devastating progressive disorder affecting motor and intellectual development. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girls, with an estimated prevalence in Australia of 1 per 10,000 females under the age of twelve years. It is a genetic disorder and occurs almost exclusively in females. In 1999, a gene (called MECP2) was identified which appears to be the cause of RTT in most girls and women with RTT. However, for 5 - 10% of RTT subjects, no gene change is found in the MECP2 gene, raising the possibility that other genes may also be responsible for RTT. Our research group has identified one of these genes. Known as STK9, little is known about this gene's function. Of great interest is the fact that our studies suggest that STK9 could also be a caus of intellectual disability in other patients, and with autism. The focus of this research project is to explore how common gene changes in STK9 are in a large number of children with RTT, intellectual disability and seizures, and autism with intellectual disability and seizures. Using cutting edge research technology, we will go on to study how STK9 interacts with MECP2 and other genes, in order to better understand how these genes may be detrimentally affecting brain function in girls and women with Rett syndrome and other neurological disorders. These studies will give us a greater understanding of normal brain development and function.Read moreRead less
Genetic And Environmental Factors In Invasive Cervical Cancer: A Twin Study.
Funder
National Health and Medical Research Council
Funding Amount
$769,637.00
Summary
Cervical cancer (neck of womb) is caused by human papillomavirus (HPV). Most women clear this very common virus. However persistent HPV infection can cause abnormal changes to cervical cells as found on Pap smears. Genetic factors may determine why such women ultimately develop cancer. A way to evaluate environmental from genetic effects is to study twins. If the risk is greater in indentical twins as compared to nonidentical it is more like to be due to genetics.
Identification Of Telomere-specific Recombination Pathways
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Human cells stop to grow when the natural ends of chromosomes become too short. One way of how cancer cells evade this growth arrest is by using a copy-mechanism to extend short chromosome ends. Ironically, this copy mechanism is usually used by cells to keep the structure of chromosomes intact in order to prevent mutations that cause cancer. Here we will study a novel protein that contributes to the copy mechanism at short chromosome ends, but not as much in normal mutation prevention.
A Genome-wide Linkage Study Of Schizophrenia In A Large Sample From Tamil Nadu, India
Funder
National Health and Medical Research Council
Funding Amount
$500,000.00
Summary
A Study of Schizophrenia in Tamil Nadu, India. The cause of schizophrenia is unknown, but there is good evidence that genes play a role. Geneticists do not fully understand how the disease is inherited, but it is very complex, and several interacting genes as well as environmental factors are probably involved. We have been recruiting families with at least two siblings with schizophrenia from a number of communities-casts in Tamil Nadu. We plan to recruit a total of 400 affected sibling familie ....A Study of Schizophrenia in Tamil Nadu, India. The cause of schizophrenia is unknown, but there is good evidence that genes play a role. Geneticists do not fully understand how the disease is inherited, but it is very complex, and several interacting genes as well as environmental factors are probably involved. We have been recruiting families with at least two siblings with schizophrenia from a number of communities-casts in Tamil Nadu. We plan to recruit a total of 400 affected sibling families, together with 400 trio families (both parents, plus their affected child). A genome-wide scan of the genetic code in all individuals will be conducted to identify chromosomal regions linked to schizophrenia. This is the first necessary step toward identifying schizophrenia susceptibility genes. If one or more genes are discovered, this will greatly improve our understanding of this disease. It will also stimulate the search for similar genes in other samples world-wide, including Australia where schizophrenia costs $2.5 billion annually in terms of treatment and loss of employment. With such a discovery, it may be possible to find better treatments that correct the basic cause of the illness and identify factors that protect against the illness.Read moreRead less
Transport Pathways Of Host-derived Iron In Schistosomes Parasites
Funder
National Health and Medical Research Council
Funding Amount
$322,091.00
Summary
This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular resp ....This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular response induced by parasite eggs trapped in body organs is the major cause of chronic human disease. We have discovered two intriguing phenomena of iron metabolism in schistosomes. Firstly, schistosomes have a greater reliance on iron than many other organisms, storing a surfeit in cells that produce the protein-rich egg shell. Secondly, a major transmembrane iron transporter of the parasites, thought to be involved in the uptake of iron, is found on the parasite external body surface and not in the parasite intestine. The extensive nutritional dependence of these worms on iron and the surface location of mediators of iron uptake raise the exciting possibility that we have uncovered a novel system that might be exploited for vaccine or drug-mediated control of these significant human parasites. If we can dissect the pathways schistosomes use to derive iron from their hosts, we may be able to generate vaccines to block this nutritional pathway, or use drugs to block embryogenesis. This project is a fact-finding mission that asks if the host-interactive tegument of these parasites is a major source of metabolic iron. Molecules we demonstrate to be present on the surface will be tested as vaccine candidates in mouse vaccine trialsRead moreRead less