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Silent but deadly – the cause of Demetz Syndrome in Tyrolean Grey cattle

Humans and animals have highly sophisticated nervous systems, which are unfortunately often prone to illness and disease.  A plethora of factors may be responsible for problems but there is increasing evidence of genetic causes for a number of conditions.  Species or races with relatively small populations are known to be particularly prone to genetic problems.  An example is the Tyrolean Grey, a cattle breed represented by only about 5,000 registered cows and known to be susceptible to a particular neurological disorder.  An international consortium of scientists involving a group at the University of Veterinary Medicine, Vienna has now uncovered the genetic basis for the condition.  Although gene sequencing suggested that the mutation in question should have no effect, the researchers found that it leads to the production of a shortened and non-functional protein.  The results are published in the prestigious online journal PLoSone.

Modern cattle breeding relies to a large extent on artificial insemination and thus a large number of cattle can often be traced to one or a few bulls.  This is part of the reason why cattle are so prone to genetic problems but it also offers hope for their treatment:  targeted breeding programmes should be able to eliminate disease-causing mutations in a very short time.  With this goal in mind, a consortium of scientists from the University of Bern, Switzerland and the Universities of Veterinary Medicine and of Natural Resources and Applied Life Sciences, Vienna investigated possible causes for the so-called Demetz Syndrome, a neurological disorder of Tyrolean Grey cattle first diagnosed by Florian Demetz in 2003 in which affected animals show lameness and ataxia, a lack of muscle coordination.

Breeding records strongly suggested that the disease had a genetic origin and initial genetic studies enabled the scientists to localize the gene mutation responsible to a relatively small region of chromosome 16 that houses the so-called MFN2 gene, known to be involved in the fusion of mitochondria.  A form of the human Charcot-Marie-Tooth disease is known to be associated with mutations in the human MFN2 gene, thus confirming the importance of the gene in neurological development.  But when they sequenced the mutated cattle MFN2 gene the researchers came up with a surprise:  the mutation was predicted to have absolutely no effect on the protein encoded by the gene.  So-called “silent mutations” are widespread in the genomes of many species and as their name implies they normally have no consequence.  So what is happening in Demetz Syndrome?

Uschi Reichart, a post-doc in the group of Mathias Müller at the University of Veterinary Medicine, Vienna, addressed the problem by examining the RNA molecules produced from the wild-type and the mutated genes.  In addition to the normal RNA molecule, she found that diseased calves make a second, much longer RNA from the same gene.  The variant RNA contains a sequence that is normally excised (“spliced”) out of the RNA transcript.  This sequence includes a “stop codon” that causes protein production to cease and as a consequence the longer RNA actually gives rise to a protein that is slightly shorter than the normal one – and is non-functional as a result.  In other words, a single-point mutation that would be expected to have no effect on the gene product is in fact directly responsible for an incorrect processing of the RNA intermediate and thus for the production of an incorrect protein.

As Reichart says, “Scientists often rely on sequence information to identify mutations.  But it is easy to miss things if you don’t also perform traditional expression studies and look at the RNA and proteins that are produced.”  A defective protein is clearly responsible for causing Demetz Syndrome in Tyrolean Grey cattle.  It should thus be possible to screen bulls for the presence of the corresponding genetic mutation and to eliminate the disease from the population.

The paper An Unusual Splice Defect in the Mitofusin 2 Gene (MFN2) is associated with Degenerative Axonopathy in Tyrolean Grey Cattle by Cord Drögemüller, Ursula Reichart, Torsten Seuberlich, Anna Oevermann, Martin Baumgartner, Kathrin Kühni Boghenbor, Michael H. Stoffel, Claudia Syring, Mireille Meylan, Simone Müller, Mathias Müller, Birgit Gredler, Johann Sölkner and Tosso Leeb has just been published in the online journal PLoSone

The scientific paper in full text online