Genetic And Phenotype Studies Of Partial Epilepsy In Gypsies
Funder
National Health and Medical Research Council
Funding Amount
$646,136.00
Summary
Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies ....Epilepsy is one of the most common serious neurological disorders, which affects more than 50 million people worldwide. Genetic research, with a major contribution from Australian researchers, has led to the discovery of many rare forms of the disease caused by mutations in single genes of large effect. However, the vast majority of cases worldwide belong to the so-called genetically complex forms, involving multiple interacting genes and environmental factors. The genetically complex epilepsies have proved particularly difficult to understand and the numerous genetic studies conducted so far have failed to produce important and replicable results. It is becoming increasingly clear that enormous genetic heterogeneity, with many rare mutations occurring in different affected subjects, will be a major obstacle to understanding the molecular basis of complex epilepsies. In this context, genetically isolated populations, which stem from a small number of ancestors, can be particularly helpful and revealing, since their limited genetic diversity means that the number of genes involved in causing complex epilepsies may be smaller and shared between individuals and families. In this study, we will analyze affected families, as well as non-familial cases of epilepsy, from a genetically isolated population - the European Roma-Gypsies. We will determine the number of potential susceptibility genes involved in familial forms, the overlap and differences between families, as well as the contribution of the genes identified in families to the development of sporadic epilepsy.Read moreRead less
Identification Of Genes For X-linked Mental Retardation.
Funder
National Health and Medical Research Council
Funding Amount
$675,228.00
Summary
We propose to identify novel heritable causes of intellectual disability using 22 large and well-characterised families from Australia. In these families we have refined the location of the genetic defect to the chromosome X and excluded the contribution of all so far known genes. We will achieve this using the technology of massive parallel sequencing. At the completion of the project we will have identified novel causes of intellectual disability and devised tests to identify them.
Investigation Into The Roles Of A Novel Vertebrate Gene, S52, In CNS Development And Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$272,389.00
Summary
Developmentally regulated genes when mutated or deleted can cause a variety of diseases including neurological diseases in humans. It is therefore important to understand the fundamental molecular genetics of development. We have discovered a novel human gene, termed S52, and its equivalent gene in the mouse. The predicted protein derived from these genes would indicate that S52 protein may interact with other proteins, possibly nerve growth factors, in the body to regulate normal development an ....Developmentally regulated genes when mutated or deleted can cause a variety of diseases including neurological diseases in humans. It is therefore important to understand the fundamental molecular genetics of development. We have discovered a novel human gene, termed S52, and its equivalent gene in the mouse. The predicted protein derived from these genes would indicate that S52 protein may interact with other proteins, possibly nerve growth factors, in the body to regulate normal development and possibly facilitate the survival of nerve cells in embryos. Strikingly, the worm C. elegans, an evoluationary very distant animal, also has a very similar gene to human. The fact that the protein has been so conserved throughout evolution supports the idea that S52 function is important in development. S52 mRNA is expressed in the developing brain, particularly in a special group of cells called the floor plate. Floor plate is a tissue that has ability to organize the patterning and differentiation of cells within the developing brain. S52 is also expressed in motor neurons in early stages of development and later in a subset of dorsal spinal cord neurons. We have mapped S52 to the short arm of human chromosome 2 (2p15-22). This region of chromosome 2 is linked to several human genetic diseases with neurological defects. Based on our preliminary data, we think S52 is not only important for normal brain development but may be mutated in a human neurological disease called Spastic Paraplegia Type 4 (SPG4) which is characterized by a degeneration of nerve cells in the spinal cord. The aim of this project is to further our understanding of the function of this gene and investigate its role in disease. This knowledge will contribute to an overall increase in our understanding of the molecular basis of brain development and neurological disease in humans.Read moreRead less
Cell Type Specification In Developing CNS: Functional Analysis Of Sox14
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are ....The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are maintained in the adult. This has been largely due to a lack of efficient and reliable methods to identify and study interneurons. We have previously discovered that a gene termed Sox14 is active in distinct interneuron groups in the embryonic brain and spinal cord. Sox14 is a member of the Sox gene family, many of which act as genetic switches to control cell and tissue development. We found that Sox14 has been extremely well conserved throughout evolution and is active in similar interneuron groups in a number of animal species. These studies led us to hypothesise that Sox14 controls a critical molecular step in the generation of certain interneurons that may be involved in reflexes, locomotion or motor coordination. In this project, we will investigate both the role of Sox14 in interneuron development and the functions of interneurons in which this gene is active. We will do so by combining modern molecular and genetic techniques with physiological approaches. This project will reveal critical molecular steps in CNS development and determine the functions of a specific group of interneurons. To this end, we will generate mouse strains in which a specific group of interneurons are genetically marked and can be manipulated during development. We envisage that these mice with 'modified brain circuits' will become unique resources for future investigations of selected interneuron types and their functions.Read moreRead less
Genome-wide Association Study Of Migraine In Women With Endometriosis
Funder
National Health and Medical Research Council
Funding Amount
$320,036.00
Summary
Typical migraine, is a frequent, debilitating and painful disorder that affects people during their most productive years (25% of females and 7.5% of males). Women suffering endometriosis (a painful gynecologic disorder affecting up to 10% of women) are at an increased risk of suffering migraine headaches. Our proposed collection of migraine phenotype data on our endometriosis cohort will facilitate identification of genes underlying both disorders.
Cis Regulatory And Functional Analysis Of Genomic Loci With Implication In Hypothalamic Obesity Using The Zebrafish As A Model System
Funder
National Health and Medical Research Council
Funding Amount
$480,936.00
Summary
Gene regulatory mutations cause changes in gene activity (expression -level, -time, -site) and therefore decide about the availability of proteins. Regulatory mutations in uncharacterized genomic loci that are related to obesity and further their effects shall be identified, with emphasis on those affecting the hypothalamic food intake control circuits. Since the energy metabolism system and the obesity candidate genes are conserved, the model system zebrafish will be used for these analyses.
PIPK2A, A Candidate Gene For Schizophrenia: Impact Of DNA Polymorphisms On Gene- And Protein Expression And -function
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the ....Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the disorder. Evidence for genetic factors has been obtained and consistently confirmed by family-, twin-, and adoption studies. After many years of research, evidence for several genes, conferring susceptibility to schizophrenia, has been obtained by gene finding approaches applied to large family samples with multiple affected members. However, these genes have to be considered as candidates until more is known about their impact on brain function resulting in schizophrenic disorders. We have dissected a gene locus on chromosome 10p detected by linkage analysis by several groups including ourselves. We obtained statistical evidence for association of DNA sequence variants in the gene encoding the enzyme phosphatidyl-4-phosphate 5-kinase with schizophrenia. This enzyme is a critical component of the phosphoinositide pathways, which are involved in cell signalling. Our aim is to identify a possible dysfunction in the pathways. We will search for mutations involved in function or dysfunction of the enzyme. We will investigate gene- and protein expression and enzyme function in lymphoblast cell cultures and in post mortem brain tissue. Our ultimate goal is to characterise the possible impairment of intracellular cell signalling and thus identify molecular targets for development of novel and specific pharmacological treatments that have the potential to replace the currently available medication which is symptom-oriented and usually accompanied by severe adverse effects.Read moreRead less
Identifying Rare Genetic Variants Conferring Susceptibility To Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$293,898.00
Summary
Recently there has been success in identifying common genetic variants that confer susceptibility to multiple sclerosis. The variants that have been discovered so far have modest effects on risk of disease, and only explain a small proportion of familial aggregation of disease. In this study we aim to identify rarer genetic variants that have stronger effects on risk of disease, using new statistical methods and new methods to sequence very large amounts of DNA.
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
Molecular Genetics Of Hereditary Motor And Sensory Neuropathy With Pyramidal Signs
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We propose to use the resources of the human genome project to locate the defective gene. In previous studies we have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this disorder forms part of the largest group of hereditary neu ....This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We propose to use the resources of the human genome project to locate the defective gene. In previous studies we have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this disorder forms part of the largest group of hereditary neuropathies yet to be defined. Because this disorder affects long spinal cord neurones, identifying the mutated gene and studying its function may shed light on possible mechanisms involved in other spinal cord diseases. This research is a systematic search and should lead to identifying the abnormal gene causing disease. Once the gene involved is known then an effective diagnostic test will be developed. When a test for the disease is available, it is likely that we will find that the disorder is more common than previously recognised. Knowledge of the function of the gene will lead to an understanding of how the disease develops and will eventually enable development of effective treatments.Read moreRead less