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
A New Paradigm For SWI/SNF Chromatin Function; The ATPase Dependent Remodeler Is A Component Of The MeCP2 Complex
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation ....DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation specific (methyl-CpG binding domain, MBD) proteins have the capacity to bind to methylated sequences and repress transcription. The mechanisms that target CpG methylation however still remain unclear. Furthermore, it is becoming increasingly evident that methyl-CpG binding proteins are not alone in silencing transcription and other epigenetic components are thought to influence transcription (namely, SWI-SNF activation complex). This grant proposal concentrates on our most recent work which demonstrates a new molecular mechanism of transcriptional repression extending the mechanism mediated by MeCP2. Our results are the first to show that the human SWI-SNF ATPase complex is a transcriptional repressor and is identified as part of the MeCP2-histone deacetylase repressor complex. This data extends the mechanistic link between DNA methylation, chromatin remodelling and transcriptional regulation. More importantly, the experimental findings could lead to a re-examination of the mechanistic basis behind MeCP2 transcriptional repression and epigenetic modification. Our findings suggest a new paradigm for SWI-SNF as a component of the MeCP2 methylation dependent silencing complex.Read moreRead less
Identification Of Genes For Non-syndromic Intellectual Disability And Walker-Warburg Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$399,984.00
Summary
Mental retardation (MR) affects 3% of people and the cause is still largely unknown. Walker-Warburg syndrome (WWS) is an inherited cause of severe MR that also includes eye and muscle disease. Recent studies suggest that there are at least ten WWS genes. This project will identify MR and WWS genes by searching for gene alteration (mutations) that affected families have in common. Knowledge of the genetic causes will lead to better understanding of normal brain development and therapies.
Understanding The Control Of Brain Development And Endocrine Function Through Central Regulation Of Gene Transcription
Funder
National Health and Medical Research Council
Funding Amount
$624,846.00
Summary
Intellectual disability affects about 2% of the Australian population. The identification of genes underlying a number of intellectual disability disorders has brought about great clinical advances. However, our knowledge of how these genes influence processes of brain development and are important for intelligence is very limited. We propose to study the function of PHF6, the gene mutated in the Börjeson-Forssman-Lehmann intellectual disability syndrome, during brain development.
The neocortex is the region of the brain that underlies all cognitive functions. Mental disorders, such as schizophrenia, occur when the communication between nerve cells in the neocortex breaks down. We propose to make electrical measurements from the thin processes of neurons that receive input from widely separated neocortical areas to understand how areas of the neocortex are functionally interlinked, with the ultimate aim to identify how these processes are disturbed in mental disorders.
The mammalian cerebral cortex is an area of the brain responsible for all higher order cognitive processes. I investigate how connections from between the two cerebral hemispheres during embryonic and foetal development, thus enabling the brain to coordinate information from the two sides of the body. Malformations of these connections cause mental retardation and sensory and motor deficits. I want to understand how these brain defects occur and how best to treat them.