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
Epigenetic modifications to the genome do not involve DNA sequence changes but modify gene expression during normal development. In diseases, like cancer, epigenetic modifications modulate gene expression in favour of disease progression. We will study the SmcHD1 gene that is involved in X chromosome inactivation, an epigenetic mechanism operating to ensure equal dosage of X-linked genes between males and females. This project will aid our understanding of chromosome structure and function.
Functional Analysis Of The X-linked Hypopituitarism (XH) Gene SOX3
Funder
National Health and Medical Research Council
Funding Amount
$331,000.00
Summary
Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development and metabolism are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow the hormone-secret ....Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development and metabolism are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow the hormone-secreting cells to arise. Changes in these pituitary formation genes results in dysfunction of the pituitary (hypopituitarism) in newborn babies. In severe cases, where the pituitary has failed to form completely, these babies are extremely ill and in some instances do not survive. We are studying families with an inherited form of hypopituitarism in which only male children are affected. This disorder is due to the presence of an extra piece of genetic material (DNA) on the X chromosome. We have recently discovered that one of the duplicated genes, SOX3, causes this disorder. The overall aim of this proposal is to understand how SOX3 causes hypopituitarism by generating a mouse model for this disorder. Analysis of this mouse model will help us to understand the clinical features of hypopituitarism and may allow us to identify previously uncharacterised anatomical defects associated with this disorder. Ultimately,we hope to develop new and improved therapies for hypopituitarism using this mouse model.Read moreRead less
A Y CHROMOSOME MODEL FOR THE SEX DETERMINING FUNCTION OF THE HUMAN ATRX GENE
Funder
National Health and Medical Research Council
Funding Amount
$272,131.00
Summary
Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to dev ....Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to develop as females, as well as causing many unrelated disorders such as alpha-thalassemia. ATRX seems to be a transcription factor that controls the activity of other genes, but it is difficult to understand how it functions because it is active in all parts of the body and mutation has many different effects in humans. However, we recently discovered that in marsupial mammals that this gene has a copy on the Y chromosome (ATRY) as well as the X (ATRX). Remarkably, there is a division of labour between ATRY, which acts only in developing gonads, and ATRX, which is active everywhere else. This testis-specific ATRY gene may reveal how ATRX interacts with other genes to make a testis, without the complications of its action in other tissues. We will therefore clone and characterize ATRX-Y and its protein product to find out when and where it acts in the sex determining pathway. We will use very large cloned pieces of the marsupial genome to discover elements controlling the testis-specific expression, and we will identify the interactions of ATRY with other proteins. The testis determination pathway is a good model for the differentiation of other human organs. Our work on ATRY will show us how this class of transcription factors is activated in different tissues during development, and how it controls other genes. This will lead to a better understanding of the genetic control of human organogenesis and the effects of mutation on human development.Read moreRead less
Pathogenesis Of Rett Syndrome: Molecular Genetics And Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$437,310.00
Summary
Rett syndrome (RS) is a devastating progressive genetic disorder affecting motor and intellectual development, and occurs almost exclusively in females. 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 girl ....Rett syndrome (RS) is a devastating progressive genetic disorder affecting motor and intellectual development, and occurs almost exclusively in females. 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. Mutations in a gene called MECP2 appears to be the cause of RS in up to 80% of affected girls and women. Now that the gene responsible for many cases of RS has been found, there are many new questions. Do all girls with RS have mutations in the MECP2 gene? Will knowing the exact mutation in the MECP2 gene be of help in predicting how severe the disorder will be in individual patients? Why is it that the brain appears to be primarily affected? Which other genes might play a role in the symptoms seen in RS? Could it be possible to develop specific treatments for RS? This research will address a number of important issues. Firstly, our genetic studies of RS subjects will result in early diagnosis, which is often delayed until after a child turns 5 years of age. Secondly, we are developing mouse models of the human disease, which will put us in a much better position in beginning to understand the biological basis of RS. Early diagnosis may enable the initiation of early treatment strategies in the short term, with the long-term goal of developing specific therapies that may potentially cure the disorder. Finally it will enable accurate genetic counselling for both the immediate and extended family members.Read moreRead less