International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F58 Mapping of Loa, A Mouse Motor Deficit Mutation, to Distal Chromosome 12

Witherden, A. S.1, Nicholson, S. J.1, Hafezparast, M.1, Bermingham, N. A.1,5, Peters, J.2, Ball, S. T.2, Rogers, D. C.3, Martin, J. E.4 and Fisher, E. M. C.1. 1Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, Norfolk Place, London W2 1PG, UK; 2Mammalian Genetics Unit, Medical Research Council, Harwell, Didcot, Oxon., OX11 ORD, UK; 3Smithkline Beecham, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK; 4Department of Morbid Anatomy, The Royal London Hospital, Whitechapel, London, E1 1BB, UK; 5Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA

Motor neuron disease is a progressive genetic disorder with 5 sufferers per 100,000 people in Europe and the UK. Approximately 20% of these cases are familial with predominantly autosomal dominant inheritance but, with the exception of SOD1, the causal genes remain unknown. Our mouse model of motor neuron degeneration will provide access to new genes involved in the pathology of these cells.

The mutant mouse called legs at odd angles (Loa) has a dominantly inherited motor neuron dysfunction. Heterozygotes have an early/mid-onset phenotype characterised by progressive loss of motor function in the hind limbs, with vacuolation of the lower motor neurons. There is no evidence of muscle pathology and heterozygotes have a normal life span. However Loa is lethal in homozygous mice within 24 hours of birth.

To map and subsequently clone the Loa gene, a large intraspecific backcross between the mutant mouse and the inbred strain C57BL/6 was set up. Affected N1 mice were backcrossed to C57BL/6 to generate over 1,000 affected N2 animals. These were used to genetically map the Loa mutation to a 1.6cM region of distal MMU12 flanked by D12Mit17 and D12Mit181.

We are constructing a contig by screening the WI/MIT820 mouse YAC library with existing markers from this region and STSs that we generate from the YACs. These YACs are also being used to isolate polymorphic microsatellites which can be genetically mapped and thereby used to narrow down the critical region.

Comparative mapping between mouse and human genomes demonstrates a syntenic region at HSA14q32. Online databases are monitored for mouse and human genes near or within the critical region. Exon trapping and cDNA selection methods will be employed to isolate candidate genes. Any genes that map to the critical region will be further analysed and sequenced in affected and wild type mice and the Loa gene identified.

 


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