Identification And Characterisation Of Novel Genes For Congenital Cataract
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Cataracts are the leading cause of blindness worldwide. The term describes a clouding of the lens which may lead to visual impairment. Congenital cataracts (present at birth) are less common than age-related cataract but the lifelong impact on vision can be severe, with a third of patients remaining legally blind. Late complications such as aphakic glaucoma may be blinding. We have shown that congenital cataracts are often inherited and have performed a population-based study in South-Eastern Au ....Cataracts are the leading cause of blindness worldwide. The term describes a clouding of the lens which may lead to visual impairment. Congenital cataracts (present at birth) are less common than age-related cataract but the lifelong impact on vision can be severe, with a third of patients remaining legally blind. Late complications such as aphakic glaucoma may be blinding. We have shown that congenital cataracts are often inherited and have performed a population-based study in South-Eastern Australia over the past 5 years to determine the causative genes. A large number of families have been involved in the study and solid progress has been made in identifying mutations in cataract genes and understanding what effect these may have on the patient's prognosis. We have recently identified a new gene in a large Australian family with a syndrome of cataract, mental retardation and teeth problems. This syndrome, known as Nance-Horan syndrome was originally described in Australia 30 years ago and we have worked with the original family to find the exact gene responsible. We already know that this gene causes the same syndrome in other families and in this project we will examine whether it can cause cataract without the other features or mental retardation without cataract. We will perform a series of experiments to learn what this gene does and how it causes the disease. We have also selected 3 other very interesting families with congenital cataracts for further study as we either know already or strongly suspect that they will enable us to identify further new genes for cataract, and in one case mental retardation. Our work in other diseases indicates that understanding the genes in severe young onset cases can give valuable clues to the causes of age-related forms and may in the future enable new ways to prevent and treat the commonest cause of worldwide blindness.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
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
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.
Investigating The Pathogenic Role Of Polyalanine Tract Expansion Mutations In The ARX Homeobox Transcription Factor.
Funder
National Health and Medical Research Council
Funding Amount
$545,619.00
Summary
Intellectual disability is frequent in the population, with as many as 1 in every 50 people in the world directly affected. ARX is one of the most frequent genes mutated in X chromosome-linked intellectual disability. Our study will specifically address the functional impact of these mutations in ARX using cell models relevant to the brain. We will also examine the contribution of other genetic changes to explain the very different symptoms seen in patients with the same gene mutation.