International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA



2.00pm – 2.15pm


Keays DA 1, Nolan P 2 , Oliver P 3, Tian G 4, Fullerton J 1, Rees M 5, Harvey RJ 6, Cowan NJ 4, Davies KE 3, Flint J 1

1 Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, United Kingdom,

2 MRC Mammalian Genetics Unit, Harwell, Didcot, United Kingdom, 3 Department of Human Anatomy and Genetics, Oxford University, Oxford, United Kingdom, 4 Department of Biochemistry, New York University Medical Center, New York, United States, 5 Swansea Clinical School, University of Wales Swansea, Singleton Park, Swansea, United Kingdom, 6 Department of Pharmacology, The School of Pharmacy, London, United Kingdom

The identification of the genes and molecular pathways that are associated with human neurobehavioral disorders has been difficult because they are heterogeneous, complex and likely involve multiple genetic loci. Mouse models that are based on intermediate signatures of psychiatric disease hold promise as an approach to dissecting the molecular basis of these disorders. N-ethyl-N-nitrosourea (ENU) mutagenesis in the mouse, when coupled to a battery of sensitive behavioural screens, is an effective way of creating and identifying novel mouse behavioral mutants. We screened 9,000 F1 mice in a dominant ENU screen for locomotor activity. We report on the identification of Jenna a hyperactive mouse mutant with an enhanced acoustic startle response. Histological analysis revealed that the Jenna mouse line also has an enlarged superior colliculus, a region of the brain implicated in regulating the startle response. We undertook positional cloning and identified linkage to a 1.2 mb region on distal chromosome 15. We have sequenced all 39 predicted and known genes in this region and identified a mutation in alpha 1 tubulin. This mutation results in a serine to glycine substitution in a highly conserved GTP binding domain of this cytoskeletal protein. We show that this results in a five-fold reduction in GTP binding affinity. We report on the screening of this gene in a cohort of humans with startle disease (hyperekplexia) and attention deficit disorder. This is the first report of alpha tubulin being associated with abnormal behavioral traits in vertebrates.

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