Conditional Gene Targeting Of An X-linked Activator Of Cytochrome C: Modelling Of An Infantile Cardiomyopathy.
Funder
National Health and Medical Research Council
Funding Amount
$183,266.00
Summary
Irregularities in heart rhythms are a significant cause of sudden and unexpected death in infants. The past few years has seen a dramatic increase in the identification of genetic abnormalities underlying such irregularities. In particular, a significant proportion of these abnormalities (known as mitochondriopathies) have been shown to be due to deficiencies or defects in the mitochondrial DNA, which encodes some of the components necessary for the generation of cellular energy stores. In contr ....Irregularities in heart rhythms are a significant cause of sudden and unexpected death in infants. The past few years has seen a dramatic increase in the identification of genetic abnormalities underlying such irregularities. In particular, a significant proportion of these abnormalities (known as mitochondriopathies) have been shown to be due to deficiencies or defects in the mitochondrial DNA, which encodes some of the components necessary for the generation of cellular energy stores. In contrast, surprisingly few examples exist where this type of disorder has been shown to be due to a defect in the DNA from the nucleus, despite the numerous components it encodes. We have strong genetic and biochemical evidence to suggest that a new gene (encoded by the nuclear DNA) underlies the sex-linked disorder, oncocytic cardiomyopathy, the major clinical features of which are sudden and irregular heart rhythms usually causing death in female infants before the age of two years. We will utilise a new and powerful genetic technique to reproduce the disorder in laboratory mice to enable a thorough investigation into how the disease manifests itself. It is hoped that this disease model will provide valuable clues towards our understanding of other disorders with sudden heart rhythm abnormalities. It may also give additional support to the likelihood that similar nuclear-encoded defects contribute to the prevalence of, and-or susceptibility to, sudden infant mortality. The novel approach taken will also, for the first time, directly investigate the mechanisms that govern the severity of presentation of the disease in females. These studies will also complement other biochemical studies that are ongoing in our laboratory and will likely have implications for the clinical presentation of numerous other X-linked genetic disorders.Read moreRead less
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
Characterisation Of Novel CDKL5 Targets: Implications For Rett Syndrome And Related Neurodevelopmental Disorders.
Funder
National Health and Medical Research Council
Funding Amount
$421,977.00
Summary
Rett syndrome (RTT) is the second most common cause of severe mental retardation in girls and women. Although two genes (MECP2 and CDKL5) responsible for RTT have been identified, we still do not understand how these genes affect brain function. The focus of this research project is to identify which proteins are controlled by CDKL5, with the express hope that a better understanding of these processes will allow us to design specfic therapies for this untreatable devasting disorder.
Functional Significance Of MeCP2 Target Genes In The Pathogenesis Of Rett Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$476,815.00
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 is a genetic disorder and contributes to a substantial proportion of girls with severe mental retardation. In 1999, a g ....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 is a genetic disorder and contributes to a substantial proportion of girls with severe mental retardation. In 1999, a gene (called MECP2) was identified which appears to be the cause of RTT in at least 80% of affected girls and women. Now that the gene responsible for many cases of RTT has been found, new questions are being asked. Why are the effects of these mutations restricted to the brain? Which other genes might play a role in the symptoms seen in RTT? The focus of this research project is to examine these 2 questions. Using new research techniques, we have identified genes that are themselves secondarily affected by mutations in the MECP2 gene. We wish to study these genes in more detail, with the aim being to gain a greater understanding of how these genes contribute to the onset of impaired brain function in girls and women with RTT. These insights are essential foundations for the development and evaluation of new and more specific therapies for this as yet incurable disorder.Read moreRead less
The Essential Nuclear Transporter Importin 13; Key Role In Brain And Testis
Funder
National Health and Medical Research Council
Funding Amount
$613,124.00
Summary
Transport into and out of the nucleus, the control centre of cells, is critical for cell function in complex organisms such as mammals. The present proposal seeks to further understanding of a novel molecule mediating nuclear transport that has a novel inhibitory form in the testis, and important roles in the lung and nervous system. The results should help basic understanding of this molecule, and relate to disease conditions such as X-linked mental retardation and childhood asthma.