International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A5. Loa (legs at odd angles) a Mouse Model of Motor Neuron Dysfunction: Mapping and Progress towards Isolation of the Causal Gene

M. Hafezparast1, A. S. Witherden1, S. J. Nicholson1, N. Bermingham1, S. Ball2, J. Peters2, D. C. Rogers3, J. E. Martin4, E. M. C. Fisher1
1Department of Neurogenetics, Imperial College School of Medicine, Norfolk Place, London W2 1PG, UK
2MRC Mammalian Genetics Unit, Didcot, Oxon, OX11 ORD, UK
3Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, UK
4Department of Histopathology, The Royal London Hospital, Whitechapel, London E1 1BB, UK

Motor neuron diseases (MNDs) are debilitating neurodegenerative disorders with an incidence of 2 in 100,000 and a prevalence of 5 in 100,000 in UK and Europe. Some of these diseases have genetic aetiology and strike both adults and children. For example, approximately 20% of cases of amyotrophic lateral sclerosis (ALS) are familial and so far only one gene, superoxide dismutase 1 (SOD1), has been identified in 10-15% of familial ALS. Thus the majority of the genes involved in the pathology of MND remain to be identified.

We have a mutant mouse, called legs at odd angles (Loa), that exhibits motor function loss in the hind limbs inherited in an autosomal dominant manner. Homozygotes die within 24 hours of birth. However, the gross anatomy of the progeny is apparently normal, indicating normal development. Heterozygous Loa/+ mice on the other hand are viable, have a normal life span, and can be identified by a characteristic clasping of the hind limbs when suspended by the tail. Compared with their wild type littermates, these mice perform significantly more poorly in the rotarod test of balance and coordination, but show increased spontaneous locomotor activity. These features of Loa mice are more profound in older animals, indicating that the Loa mutation results in a progressive motor function deficit. Histopathological analysis has revealed a significant decrease in the number of anterior horn cells in Loa/+ mutants compared with wild type littermates, but there is no evidence of muscle denervation in Loa/+ mice, indicating that the pathology of the Loa mutation is a neuropathy.

A large intraspecific backcross between Loa/+ and the C57BL/6 inbred mouse strain was set up. Only affected N1 animals were backcrossed to C57BL/6 to generate more than 1,000 N2 affected mice. The N2 progeny were used to map the Loa mutation to an interval of approximately 1.6 cM in the distal region of Mmu12. This interval is flanked by D12Mit17 and D12Mit181. We have constructed YAC/PAC/BAC contigs of the regions flanking the critical region and are generating more STS markers for chromosome walking and bridging the gap that exists within our contig of the Loa region. The STS markers are also analysed for simple sequence repeat and single nucleotide polymorphisms to narrow the critical region. The mouse and human comparative map, EST and other bioinformatics resources are routinely surveyed for identification of candidate genes near or within the critical region. Any candidate genes that map to the Loa critical region will be further analysed and if not excluded, they will be sequenced in affected and wild type mice for the identification of the Loa gene.

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