A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acetylglucosamine transporter, causes complex vertebral malformation

Bo Thomsen; Per Horn; Frank Panitz; Emøke Bendixen; Anette H. Petersen; Lars-Erik Holm; Vivi H. Nielsen; Jørgen S. Agerholm; Jens Arnbjerg; Christian Bendixen

doi:10.1101/gr.3690506

A missense mutation in the bovine SLC35A3 gene, encoding a UDP-N-acetylglucosamine transporter, causes complex vertebral malformation

¹ Department of Genetics and Biotechnology, Danish Institute of Agricultural Sciences, DK-8830 Tjele, Denmark
² Department of Animal Health, Welfare and Nutrition, Danish Institute of Agricultural Sciences, DK-8830 Tjele, Denmark
³ Department of Veterinary Pathobiology, Royal Veterinary and Agricultural University, DK-1870 Frederiksberg C, Denmark
⁴ Department of Radiology, Royal Veterinary and Agricultural University, DK-1870 Frederiksberg C, Denmark

Abstract

The extensive use of a limited number of elite bulls in cattle breeding can lead to rapid spread of recessively inherited disorders. A recent example is the globally distributed syndrome Complex Vertebral Malformation (CVM), which is characterized by misshapen and fused vertebrae around the cervico-thoracic junction. Here, we show that CVM is caused by a mutation in the Golgi-resident nucleotide-sugar transporter encoded by SLC35A3. Thus, the disease showed complete cosegregation with the mutation in a homozygous state, and proteome patterns indicated abnormal protein glycosylation in tissues of affected animals. In addition, a yeast mutant that is deficient in the transport of UDP-N-acetylglucosamine into its Golgi lumen can be rescued by the wild-type SLC35A3 gene, but not by the mutated gene. These results provide the first demonstration of a genetic disorder associated with a defective SLC35A3 gene, and reveal a new mechanism for malformation of the vertebral column caused by abnormal nucleotide-sugar transport into the Golgi apparatus.

Footnotes

[The sequence data from this study has been submitted to GenBank under accession no. AY160683. The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: C.B. Hirschberg, C. Abeijon, and P.J. de Jong.]
Article published online ahead of print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.3690506. Freely available online through the Genome Research Immediate Open Access option.
↵5 Corresponding author. E-mail christian.bendixen{at}agrsci.dk; fax 45-89991300.
- Accepted August 17, 2005.
- Received January 12, 2005.
Cold Spring Harbor Laboratory Press