The Role Of Sox8 In Sex Determination And Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
We have discovered a new gene called Sox8. This gene is very closely related to another gene, Sox9, that is known to be a critical factor in determining whether an embryo develops as a male or female by specifying whether the embryo makes testes or ovaries. We have found that Sox8, like Sox9, is active in the cell type in fetal testes known to be important for the development of maleness, at around the time when the male-female decision is being made. We therefore believe that Sox8 is an importa ....We have discovered a new gene called Sox8. This gene is very closely related to another gene, Sox9, that is known to be a critical factor in determining whether an embryo develops as a male or female by specifying whether the embryo makes testes or ovaries. We have found that Sox8, like Sox9, is active in the cell type in fetal testes known to be important for the development of maleness, at around the time when the male-female decision is being made. We therefore believe that Sox8 is an important part of the genetic chain of events leading to normal male development. We aim to study how Sox8 exerts its effects on male development. We have also found that in humans, Sox8 is located in a chromosomal region associated with a developmental disease syndrome characterized by mental retardation, facial defects and anomalies of male sexual development. Sox8 is active in mouse embryos in all the tissues affected by the human disease. We believe defects in SOX8 in humans are largely responsible for this disease, called ATR-16 syndrome. We will test whether patients with ATR-16 have defects involving SOX8 in their DNA in order to test this theory. In summary, we believe we have found a new human disease gene which will further our understanding of how developmental diseases arise in the embryo. In addition, this work will shed light on the process of sexual development, a significant healthcare problem in view of the fact that defects in sexual development are among the most common forms of birth defects.Read moreRead less
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.
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
Mapping Neurodevelopmental Disorders In A Zebrafish Model
Funder
National Health and Medical Research Council
Funding Amount
$2,760,520.00
Summary
The way in which the brain develops differently in neurodevelopmental disorders such as autism is hard to reveal in humans, but can be addressed in a zebrafish model. Using cutting-edge imaging and computational techniques, this project will investigate how neural representations of the world develop differently between normal zebrafish and zebrafish mutant for a gene that causes autism. This will provide new insights into the mechanisms of altered circuit development in autism.
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
Novel Fragile X Syndrome Prevalence Estimates In 100,000 Australian Newborns, Prognostic And Health-economic Outcomes: A Retrospective Newborn Screening Study
Funder
National Health and Medical Research Council
Funding Amount
$769,866.00
Summary
Fragile X syndrome (FXS) is a common heritable cause of intellectual disability and co-morbid autism, caused by epigenetic silencing of the FMR1 gene. This will be the world’s largest FXS mutation prevalence study conducted in 100,000 newborns using a novel test targeting epigenetic changes, and will also explore the prognostic outcomes, costs and benefits associated with FXS newborn screening, providing conclusions regarding expanding the current newborn screening in Australia to include FXS.