Abstract
The dystonin/Bpag1 gene encodes several tissue-specific alternatively spliced transcripts that encode cytoskeletal binding proteins. These various isoforms are necessary for maintaining the structural integrity of epithelial, neural, and muscle tissues. Mutations in the dystonin/Bpag1 gene cause dystonia musculorum (dt), a hereditary neuropathy of the mouse characterized by the progressive degeneration of sensory neurons. Several dt mutant alleles exist, most of which have arisen through spontaneous mutations. In this article we demonstrate that the dt locus encodes 107 exons spanning 400 kb. The high frequency of occurrence of spontaneous dt mutants may therefore be a result of the large size of the gene. Analysis of genomic DNA from several dt spontaneous mutant alleles, dt 24J, dt 27J, dt Alb, and dt Frk, shows a deletion of the central portion of the gene in dt Alb but no large rearrangements or deletions in the other alleles. These other alleles likely have small deletions or rearrangements, or point mutations. To determine the impact of the known and unknown mutations on transcript levels, RT-PCR was performed to detect various coding regions of the dystonin/Bpag1 transcripts in brain and muscle from multiple dt alleles: dt Tg4, dt Alb, dt 24J, dt 27J, and dt Frk. With the exception of dt Frk, reduced transcript levels were observed for all alleles tested. Such alterations likely result in reduced or absent dystonin/Bpag1 protein levels. Thus, distinct genetic defects lead to a common outcome of reduced transcript expression causing the same phenotype in multiple dt alleles.
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Acknowledgments
The authors thank Martine Mathieu and Yves De Repentigny for technical assistance during the course of this work. Drs. Messer and Frankel are acknowledged for their contribution of the Alb and Frk alleles of dt. The work in this study was supported by a grant from the Canadian Institutes of Health Research (CIHR). MP held a Multiple Sclerosis Society of Canada Studentship and CBL was a CIHR Postdoctoral Fellow.
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Madeline Pool and Céline Boudreau Larivière contributed equally to this work.
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Pool, M., Boudreau Larivière, C., Bernier, G. et al. Genetic alterations at the Bpag1 locus in dt mice and their impact on transcript expression. Mamm Genome 16, 909–917 (2005). https://doi.org/10.1007/s00335-005-0073-4
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DOI: https://doi.org/10.1007/s00335-005-0073-4