title: A new mouse model of Canavan leukodystrophy displays hearing impairment due to central nervous system dysmyelination.
abstract: Canavan disease is a leukodystrophy caused by mutations in the ASPA gene. This gene encodes the enzyme that converts N-acetylaspartate into acetate and aspartic acid. In Canavan disease, spongiform encephalopathy of the brain causes progressive mental retardation, motor deficit and death. We have isolated a mouse with a novel ethylnitrosourea-induced mutation in Aspa. This mutant, named deaf14, carries a c.516T>A mutation that is predicted to cause a p.Y172X protein truncation. No full-length ASPA protein is produced in deaf14 brain and there is extensive spongy degeneration. Interestingly, we found that deaf14 mice have an attenuated startle in response to loud noise. The first auditory brainstem response peak has normal latency and amplitude but peaks II, III, IV and V have increased latency and decreased amplitude in deaf14 mice. Our work reveals a hitherto unappreciated pathology in a mouse model of Canavan disease, implying that auditory brainstem response testing could be used in diagnosis and to monitor the progression of this disease.
authors.affiliation: Murdoch Childrens Research Institute, 50 Flemington Road, Parkville, VIC 3052, Australia. The HEARing Cooperative Research Centre, 550 Swanston Street, University of Melbourne, VIC 3010, Australia. marina.carpinelli@mcri.edu.au.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Carpinelli
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Voss
authors.affiliation: Murdoch Childrens Research Institute, 50 Flemington Road, Parkville, VIC 3052, Australia. The HEARing Cooperative Research Centre, 550 Swanston Street, University of Melbourne, VIC 3010, Australia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Manning
authors.affiliation: Murdoch Childrens Research Institute, 50 Flemington Road, Parkville, VIC 3052, Australia.
authors.forename: Ashwyn A
authors.initials: AA
authors.lastname: Perera
authors.affiliation: The HEARing Cooperative Research Centre, 550 Swanston Street, University of Melbourne, VIC 3010, Australia. Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Cooray
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: Murdoch Childrens Research Institute, 50 Flemington Road, Parkville, VIC 3052, Australia. Department of Genetics, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Burt
mesh_terms: D000818:Animals; D017825:Canavan Disease / Q000503:physiopathology*; D002490:Central Nervous System / Q000473:pathology*; D003711:Demyelinating Diseases / Q000503:physiopathology*; D004195:Disease Models, Animal; D006311:Hearing Disorders / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains
keywords: Aspa; Aspartoacylase; Canavan disease; ENU mutagenesis; Leukodystrophy; Myelin