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

F4 Mutation by Generation of a Novel Hybrid Gene in the Neurological Mutant flailer

Julie M. Jones1, Jian-Dong Huang2, Valerie Mermall4, Bruce Hamilton3, Mark S. Mooseker4, Andrew Escayg1, Neal G. Copeland2, Nancy A. Jenkins2 and Miriam H. Meisler1. 1Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0618; 2ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702; 3Department of Medicine, University of California, San Diego, California; 4Department of MCD-Biology, Yale University, New Haven, Connecticut 06520

We have identified a novel mutation in the spontaneous neurological mutant flailer. Homozygous flailer mice exhibit a movement disorder that includes ataxia and opisthotonos. The symptoms are most severe between 2 and 4 weeks of age; there is progressive recovery and adults are only mildly affected. flailer arose spontaneously at the Jackson Laboratory in 1971, and was originally classified as the tb2J allele of the tumbler mutation on the basis of noncomplementation. We have mapped the flailer mutation to the central region of mouse chromosome 9, close to Myo5a. Since mutations in Myo5a are responsible for similar neurological dysfunction in the 'dilute neurological' mutations, we examined Myo5a expression in flailer mice. In addition to the three normal brain transcripts, flailer mice express three unique transcripts. Molecular analysis demonstrated that the abnormal transcripts contain the first two exons of an adjacent gene that are fused in frame with the 3' half of the Myo5a transcript. Analysis of genomic DNA demonstrated that the junction site in the hybrid gene is located within an intron of each parental gene. Functional copies of both parental genes are also present on the flailer chromosome, which could have been generated by unequal recombination or by duplication of a chromosome segment followed by internal deletion. The predicted hybrid protein contains the 83 amino-terminal amino acid residues from the adjacent gene and the 711 carboxy-terminal residues of Myo5a, including the putative cargo-binding tail domain. The predicted 85 kDa hybrid protein can be detected with antibodies to the tail domain of Myo5a, and is present at a concentration comparable to the wildtype Myo5a protein. The mechanism of action of the hybrid protein appears to be competition with wildtype Myo5a for transport of vesicles of smooth endoplasmic reticulum (SER), since SER is missing from dendritic spines of cerebellar Purkinje cells in affected flailer mice. Effective competition by constructs containing the Myo5a tail domain has been demonstrated by others in transfected cells. The neurological disorder in flailer mice is probably secondary to altered intracellular calcium homeostasis in the Purkinje cells. This is the first reported example of germline mutation by exon swapping between unrelated genes, a process thought to be responsible for generating new gene function on an evolutionary time scale.


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