Significance Of Low-level Mosaicism To Intellectual Disability In Paediatric Disorders
Funder
National Health and Medical Research Council
Funding Amount
$483,402.00
Summary
My vision for the next 4 years is to improve outcomes for children and their families with inherited disorders associated with intellectual disability (ID) and autism through earlier diagnosis and intervention. This is of great importance with annual costs of ID close $14.72 billion to the Australian health system, and missed or delayed diagnoses being a significant problem, as ID is found in 1.7% of births, where a specific cause is currently identified in less than half.
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
Prevalence And Characterisation Of FMR1 Gene's Premutation Carriers Amongst Older Males Presenting With Tremor/ataxia
Funder
National Health and Medical Research Council
Funding Amount
$199,450.00
Summary
The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the ....The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the FMR1 specific protein product (FMRP), the pathways from premutation to a neurological disorder are unknown. In this disorder, neurological dysfunction is associated with brain atrophy visible in magnetic resonance (MRI) images. Molecular studies showed increased levels of 'messenger' RNA (mRNA), which indicates overexpression of FMR1 gene . Our own study showed significantly increased (41.7%) prevalence of neurological involvement in male premutation carriers aged >50, compared with age-matched norms. Moreover, a screening of patients with two neurological disorders associated with tremor showed a significant increase of premutation carriers (5%- 22%). The aim of this study is to test hypotheses about the association of late-onset neurological disorders of unknown cause presenting tremor and imbalance, with a fragile X premutation in males, by screening for the presence of this premutation; and then conducting a full assessment of the identified premutation carriers, including detailed neurological, neuropsychological and MRI tests, to establish the spectrum of neurological involvement. This involvement will be correlated with the molecular (DNA, mRNA, FMRP) findings. The results will contribute to understanding the mechanisms of neurological involvement caused by this premutation. Moreover, estimation of the prevalence of this premutation in relevant neurological disorders will impact on standard diagnostic, and possibly future treatment approaches in neurology clinics.Read moreRead less
Prevalence And Genetic Mechanisms Of Neurological And Gynaecological Changes In Women Carrying Small FMR1 Expansions
Funder
National Health and Medical Research Council
Funding Amount
$411,895.00
Summary
Fragile X syndrome is one of the commonest genetic forms of mental retardation. The abnormal gene is passed from mothers to their sons or daughters, on their X chromosome. The gene abnormality is unstable, tending to worsen each time it is passed on. But if this gene abnormality is passed from fathers to their daughters, it does not worsen. Therefore, grandfathers of the affected children on their mother's side, as well as the mothers, may carry a mildly abnormal gene (a premutation), insufficie ....Fragile X syndrome is one of the commonest genetic forms of mental retardation. The abnormal gene is passed from mothers to their sons or daughters, on their X chromosome. The gene abnormality is unstable, tending to worsen each time it is passed on. But if this gene abnormality is passed from fathers to their daughters, it does not worsen. Therefore, grandfathers of the affected children on their mother's side, as well as the mothers, may carry a mildly abnormal gene (a premutation), insufficient to cause mental retardation. However, it has recently been discovered that these grandfathers may develop a syndrome (FXTAS) of tremor, incoordination, slowness of movements and mild dementia in their later years. Women were thought to be protected, as they carry TWO X chromosomes, one of which is normal even if the other has a premutation. But very recent reports suggest that they may also develop the FXTAS syndrome, as well as early menopause. This study aims to see how common and severe these abnormalities are in women who carry the premutation, using clinical, MRI and electronic measurements, and to relate the abnormalities to the severity of the gene malfunction and familial predisposition.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