Characterization Of A Novel Human X-linked Gene RBMX, A Candidate For X-linked Mental Retardation
Funder
National Health and Medical Research Council
Funding Amount
$356,870.00
Summary
We recently discovered a novel gene (which we have called RBMX for RNA-binding protein, X chromosome) on the human X chromosome. Its function is quite unknown, but it is active in all tissues, and it has changed very little in evolution, so we think it must have an important function in human development. Genes with a similar sequence bind to RNA and convert it to its final active form, so RBMX may have a similar role. Other RNA-binding proteins are active in the brain, so we suspect that RBMX m ....We recently discovered a novel gene (which we have called RBMX for RNA-binding protein, X chromosome) on the human X chromosome. Its function is quite unknown, but it is active in all tissues, and it has changed very little in evolution, so we think it must have an important function in human development. Genes with a similar sequence bind to RNA and convert it to its final active form, so RBMX may have a similar role. Other RNA-binding proteins are active in the brain, so we suspect that RBMX may be involved in brain development and learning. The RBMX gene is also interesting because it has a copy called RBMY on the human Y chromosome, which is thought to have a critical (unknown) function in sperm production. Of particular note is our finding that RBMX maps to the long arm of the human X chromosome at Xq26. This is a region that contains several inherited mental retardation syndromes called X linked mental retardation (XLMR) which are carried by females and manifest in males. At least eight XLMR syndromes have been mapped to human Xq26. Several of the syndromes have characteristic skeletal and facial abnormalities, as well as a range of other anomalies.. We will completely characterise the human RBMX gene. As well as giving us fresh clues to its function, this will allow us to make a mouse strain that lacks the gene (knockout) so we can see whether it is critical for life, and if it is involved in brain development and learning. Identification of an XLMR gene coding for an RNA binding protein will shed light on the role of RNA metabolism in the brain, and the effect of disruptions of RNA processing on mental function. We will then screen the RBMX gene in families with XLMR syndromes, to look for RBMX mutations in patients which may cause XLMR. If mutations in RBMX cause one or more XMLR phenotypes, it will be possible to use this knowledge to diagnose the condition and detect carriers.Read moreRead less
Functional Evaluation Of BRCA1 & BRCA2 Unclassified Sequence Variants And Identification Of Critical Pathogenic Domains.
Funder
National Health and Medical Research Council
Funding Amount
$331,312.00
Summary
The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the se ....The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the sequence change. Consequently, it is not possible to offer informative genetic counselling to these women or their at-risk family members. Assessment of the potential pathogenicity and functional significance of these unclassified sequence variants will be directly useful with regard to the clinical management of these women and their families, and will develop our current understanding of how different domains of these genes contribute to their role as cancer susceptibility genes.Read moreRead less
The Identification Of Novel Genes Involved In The Initiation And Development Of Thyroid Neoplasia
Funder
National Health and Medical Research Council
Funding Amount
$227,545.00
Summary
Thyroid cancer is the most frequently diagnosed endocrine malignancy, comprising 1% of all human malignancy. However, its actual occurrence indicated by autopsy studies may be as high as 10%. To date, a number of genes, both oncogenes (genes that are inappropriately switched on and take part in the process of tumour development) and tumour suppressor genes (genes that are switched off and lose their protective role against tumour development), have been implicated in the development of thyroid c ....Thyroid cancer is the most frequently diagnosed endocrine malignancy, comprising 1% of all human malignancy. However, its actual occurrence indicated by autopsy studies may be as high as 10%. To date, a number of genes, both oncogenes (genes that are inappropriately switched on and take part in the process of tumour development) and tumour suppressor genes (genes that are switched off and lose their protective role against tumour development), have been implicated in the development of thyroid cancer. However mutations, mistakes in the genetic code, of these genes account for only a small percentage of thyroid tumours and none of these genes have been shown to be useful as clear prognostic markers for tumour progression or aggressiveness. The merging of the 2 fields of cytogenetics (the study of chromosomes) and molecular genetics (the study of genes at the DNA and RNA level) has strengthened our ability to understand the process of tumour development. We are proposing use of a technique called Comparative Genomic Hybridisation to aid in the identification of new genes associated with tumour development in both benign and malignant thyroid disease. This technique has already been used to aid in the location of genes with a role in ovarian and brain cancer and in some familial syndromes characterised by breast and gastrointestinal malignancies. This method involves the detection of regions of chromosomal amplifications or deletions in tumour DNA that is fluorescently labelled (green), mixed with normal human DNA also fluorescently labelled (red). If the tumour contains regions of amplification (likely housing an oncogene), analyses show increased green fluorescence and if deletions are present (likely housing a tumour suppressor gene), analyses show increased red fluorescence. Chromosomal regions identified by this method will be further analysed to identify the precise genes they contain and establish a role for these genes in the development of thyroid tumours.Read moreRead less
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.
Communication Of Genetic Information In Families: A Randomised Controlled Trial Of A Genetic Counselling Intervention.
Funder
National Health and Medical Research Council
Funding Amount
$359,728.00
Summary
The amount of genetic testing information available to Australians has exploded as a result of the human genome project. Our multi-disciplinary team will investigate the most acceptable and feasible way for important genetic information to be transmitted in families. This study will be a world first trial of a genetic counselling intervention which aims to help patients and health professionals communicate life-changing information in families where there is a serious genetic condition.
Treatment Of Lysosomal Storage Disorder Patients By Drug-enhanced Premature Stop Codon Read-through
Funder
National Health and Medical Research Council
Funding Amount
$431,764.00
Summary
Lysosomal storage disorders are a devastating set of genetic diseases with very severe clinical symptoms. In this project, we will investigate a new treatment strategy that is non-invasive and that will be applicable for a wide range of lysosomal storage disorder patients. The therapy will over-ride the molecular genetic lesion and will be preferentially targeted for patients who are at the severe end of the clinical spectrum, where treatment options are currently limited.
Development Of A Safe And Effective Treatment For Neuropathology In MPS IIIA.
Funder
National Health and Medical Research Council
Funding Amount
$665,320.00
Summary
MPS IIIA is an inherited disorder that results in progressive brain disease in affected children. The disorder cannot be treated at present because it has not been possible to find an effective way to deliver treatment to the brain. This project seeks to evaluate a method to overcome this problem. Findings in this project can be applied to other, similar disorders that affect the brain.
Genomic And Functional Analyses Of A Novel Gene Implicated In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$732,439.00
Summary
We have recently discovered a novel gene that contributes to the development of juvenile diabetes. Unfortunately, very little is known about the function of this gene. To better understand how this gene affects the immune system and contributes to disease, we have generated a unique mouse strain that has a dysfunctional copy of this gene. These mice will enable us to characterise this gene and potentially establish a new area of research in diabetes prevention.
Liver Cell Transplantation For The Treatment Of Liver Based Metabolic Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$444,143.00
Summary
We propose to investigate the role of liver cell transplantation (LCT) for the therapy of inherited liver-based metabolic diseases using a methylmalonic aciduria (MMA) mouse model. LCT provides an exciting alternative to whole organ transplantation. Initially it was considered liver cells would be immunopriviledged. This has not proven to be the case. Immune modulation will be important. We will also examine immune modulation using antibodies to optimise longterm survival of allogeneic cells.
The Molecular Basis For The Increased Incidence Of Thrombosis Associated With The Prothrombin G20210A Gene Polymorphism
Funder
National Health and Medical Research Council
Funding Amount
$213,838.00
Summary
Prothrombin is an important enzyme involved in the formation of blood clots. Recently, a mutation was discovered in the prothrombin gene. This mutation occurs at a frequency of 2% in the normal population but occurs at an increased frequency (6%) in patients with thrombosis and is associated with an increase in the levels of prothombin in the blood. The position of this mutation in the prothrombin gene corresponds to the last residue of the prothrombin mRNA. We have preliminary data to suggest t ....Prothrombin is an important enzyme involved in the formation of blood clots. Recently, a mutation was discovered in the prothrombin gene. This mutation occurs at a frequency of 2% in the normal population but occurs at an increased frequency (6%) in patients with thrombosis and is associated with an increase in the levels of prothombin in the blood. The position of this mutation in the prothrombin gene corresponds to the last residue of the prothrombin mRNA. We have preliminary data to suggest that this mutation results in the prothrombin mRNA being more stable, which in turn allows for the production of more prothrombin protein, leading to an increased risk of developing a blood clot. The aim of this project is to explore the mechanisms leading to the elevated levels of prothrombin observed patients with this mutation.Read moreRead less