Disease Gene Discovery And Improved Genetic Diagnosis In Neuromuscular Disorders
Funder
National Health and Medical Research Council
Funding Amount
$473,321.00
Summary
Paediatric nerve and muscle disorders result in weakness, chronic disability and often early death. Over half of all affected children do not yet have a genetic diagnosis. This project will use advanced sequencing technology to increase genetic diagnosis rates and identify new disease-causing genes. This will result in improved patient care and a better understanding of the biological pathways altered by these disorders. It will also facilitate the identification of targets for future therapies.
Genetic Bases For Charcot-Marie-Tooth And Hereditary Sensory Type 1 Neuropathies
Funder
National Health and Medical Research Council
Funding Amount
$618,055.00
Summary
This project aims to identify the defective gene in a hereditary disease of peripheral nerve. The hereditary disorders of peripheral nerve form the commonest group of human genetic diseases, collectively called Charcot-Marie-Tooth neuropathy. Although few hereditary nerve diseases are fatal most cause lifelong disability. All cause weakness of the lower legs and later weakness and wasting of the muscles of the arm and hand. Affected individuals have difficulty running, frequent falls with gradua ....This project aims to identify the defective gene in a hereditary disease of peripheral nerve. The hereditary disorders of peripheral nerve form the commonest group of human genetic diseases, collectively called Charcot-Marie-Tooth neuropathy. Although few hereditary nerve diseases are fatal most cause lifelong disability. All cause weakness of the lower legs and later weakness and wasting of the muscles of the arm and hand. Affected individuals have difficulty running, frequent falls with gradually increasing disability eventually requiring splints and other walking aids. We propose to use the newly developed resources of the human genome project to locate the defective gene. In previous studies we have used these methods to locate the defective genes of 2 other hereditary diseases of nerve. In this study we propose to investigate a newly recognised form of CMT called intermediate CMT. Intermediate CMT has characteristics intermediate between the better known forms of CMT affecting the nerve itself (the axon) or the nerve insulation (the surrounding myelin sheath). The disorder may therefore affect both components of nerve. The affected gene may mediate communication between the nerve and its sheath. This research should give valuable insight into the mechanisms responsible for the maintenance of normal nerve. Finding the gene may therefore have relevance to many other diseases of nerve. This research is a systematic search and should lead to the abnormal gene causing the disease. Once the gene involved is known then an effective test will be developed. When we can test for the disease, we probably will find that the disorder is much more common than previously recognised. Knowledge of the function of this gene will lead to an understanding of how the disease develops and will eventually lead to effective treatments.Read moreRead less
Gene Identification For Inherited Peripheral Neuropathies By Applying Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$605,058.00
Summary
Our goal is to study the biology underlying the death of motor and sensory nerves by identifying novel genes causing Charcot-Marie-Tooth (CMT) neuropathy. Using massively parallel sequencing we will systematically analyse the novel DNA changes througout the genome in CMT families in which the underlying gene mutation is unknown. Discovery of genes causing inherited peripheral neuropathies will elucidate mechanisms causing neurodegeneration and lead to targeted therapeutic treatment strategies to ....Our goal is to study the biology underlying the death of motor and sensory nerves by identifying novel genes causing Charcot-Marie-Tooth (CMT) neuropathy. Using massively parallel sequencing we will systematically analyse the novel DNA changes througout the genome in CMT families in which the underlying gene mutation is unknown. Discovery of genes causing inherited peripheral neuropathies will elucidate mechanisms causing neurodegeneration and lead to targeted therapeutic treatment strategies to prevent the death of motor and sensory nerves.Read moreRead less
Molecular Genetics Of Hereditary Motor And Sensory Neuropathy With Pyramidal Signs
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We propose to use the resources of the human genome project to locate the defective gene. In previous studies we have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this disorder forms part of the largest group of hereditary neu ....This project aims to determine the molecular cause of hereditary motor neuropathies with pyramidal signs by chromosomal linkage studies and to screen suitable families to locate genes with disease causing mutations. We propose to use the resources of the human genome project to locate the defective gene. In previous studies we have used these methods to identify genes of two other hereditary diseases of nerve. Our data suggests that this disorder forms part of the largest group of hereditary neuropathies yet to be defined. Because this disorder affects long spinal cord neurones, identifying the mutated gene and studying its function may shed light on possible mechanisms involved in other spinal cord diseases. This research is a systematic search and should lead to identifying the abnormal gene causing disease. Once the gene involved is known then an effective diagnostic test will be developed. When a test for the disease is available, it is likely that we will find that the disorder is more common than previously recognised. Knowledge of the function of the gene will lead to an understanding of how the disease develops and will eventually enable development of effective treatments.Read moreRead less
The Role Of Proteases In Deafness; Generation Of A Knockout Mouse For Tmprss3 As A Model Of Autosomal Recessive Deafness
Funder
National Health and Medical Research Council
Funding Amount
$70,880.00
Summary
Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited ....Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited defects are responsible for most cases of genetic deafness (70%) and patients have no other medical problems, indicating that only the inner ear is affected. Genes previously identified for genetic forms of deafness can be broadly classified as either ion channels (e.g. connexins) or structural proteins (e.g. myosins and collagens). We recently identified a novel gene, a transmembrane serine protease, TMPRSS3, which is mutated both in familial and sporadic cases of deafness. Different classes of mutations may cause either deafness from birth or childhood onset deafness. Thus, reduced expression or abnormal function of TMPRSS3 may be involved in age-related hearing loss. This discovery was the first description of a protease involved in hearing loss and the first gene family involved in congenital deafness for which a ready hypothesis for involvement in age-related hearing loss can be made. We will generate and characterize a mouse model to investigate the role of TMPRSS3 in inner ear function and development. We will also isolate and characterize additional members of the transmembrane protease gene family to investigate further the role of proteases in both genetic and age-related hearing loss. This may lead to a greater understanding of the function of the auditory system and, eventually, to new therapeutic protocols.Read moreRead less