Abstract
Bovine spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disease, has been mapped at moderate resolution to the distal part of Chromosome 24. In this article we confirm this location and fine-map the SMA locus to an interval of approximately 0.8 cM at the very distal end of BTA24. Despite remarkable similarity to human SMA, the causative gene SMN can be excluded in bovine SMA. However, the interval where the disease now has been mapped contains BCL2, like SMN an antiapoptotic factor, and shown to bind to SMN. Moreover, knockout mice lacking the BCL2 gene show rapid motor neuron degeneration with early postnatal onset, as observed in bovine SMA. A comparative cattle/human map of the distal end of BTA24, based on the emerging bovine genome sequencing data, shows conserved synteny to HSA18 with hints of a segmental duplication and pericentic inversion just after the last available bovine marker DIK4971. This synteny lets us conclude that SMA is in immediate vicinity of the telomere. Candidate gene analysis of BCL2, however, excludes most of this gene, except its promoter region, and draws attention to the neighboring gene VPS4B, part of the endosomal protein-sorting machinery ESCRT-III which is involved in several neurodegenerative diseases.
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Acknowledgments
The authors thank the Swiss Brown Cattle Breeders’ Federation, and especially Oskar Grüter, for giving access to the Brown Swiss Database of hereditary defects and for providing samples of swiss SMA calves and carriers. They also thank Walter Glawischnik (AGES Austria), Stefan Rist (AHG Kempten), Matthias Kelz (Rinderbesamungsgenossenschaft Memmingen), and Hermann Zuchtriegel (Besamungsstation Greifenberg) for providing samples of SMA cases and carriers. This work was funded by a grant from Deutsche Forschungsgemeinschaft DFG (project KR 2866/1).
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Stefan Krebs and Ivica Medugorac contributed equally to this work and agreed to be considered as first authors.
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Krebs, S., Medugorac, I., Russ, I. et al. Fine-mapping and candidate gene analysis of bovine spinal muscular atrophy. Mamm Genome 17, 67–76 (2006). https://doi.org/10.1007/s00335-005-0102-3
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DOI: https://doi.org/10.1007/s00335-005-0102-3