An Unusual Splice Defect in the Mitofusin 2 Gene (MFN2) Is Associated with Degenerative Axonopathy in Tyrolean Grey Cattle

Cord Drögemüller,Kathrin Kühni Boghenbor,Michael H Stoffel,Tosso Leeb,Martin Baumgartner,Mireille Meylan,Torsten Seuberlich,Mathias Müller,Birgit Gredler,Anna Oevermann,Ursula Reichart,Johann Sölkner,Simone Müller,Claudia Syring

doi:10.1371/journal.pone.0018931

Abstract

Tyrolean Grey cattle represent a local breed with a population size of ∼5000 registered cows. In 2003, a previously unknown neurological disorder was recognized in Tyrolean Grey cattle. The clinical signs of the disorder are similar to those of bovine progressive degenerative myeloencephalopathy (weaver syndrome) in Brown Swiss cattle but occur much earlier in life. The neuropathological investigation of an affected calf showed axonal degeneration in the central nervous system (CNS) and femoral nerve. The pedigrees of the affected calves suggested a monogenic autosomal recessive inheritance. We localized the responsible mutation to a 1.9 Mb interval on chromosome 16 by genome-wide association and haplotype mapping. The MFN2 gene located in this interval encodes mitofusin 2, a mitochondrial membrane protein. A heritable human axonal neuropathy, Charcot-Marie-Tooth disease-2A2 (CMT2A2), is caused by MFN2 mutations. Therefore, we considered MFN2 a positional and functional candidate gene and performed mutation analysis in affected and control Tyrolean Grey cattle. We did not find any non-synonymous variants. However, we identified a perfectly associated silent SNP in the coding region of exon 20 of the MFN2 gene. This SNP is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron. This splicing defect represents a potential explanation for the observed degenerative axonopathy. Marker assisted selection can now be used to eliminate degenerative axonopathy from Tyrolean Grey cattle.

Highlights

Spontaneous mutants in domestic animals provide insights on genotype-phenotype correlations, which are relevant for biomedical research [1]
The animal showed mild ambulatory paraparesis with moderate to severe ataxia most pronounced in the pelvic limbs
We could quickly identify a relatively small interval for the degenerative axonopathy mutation in Tyrolean Grey cattle containing less than 40 genes

Summary

Introduction

Spontaneous mutants in domestic animals provide insights on genotype-phenotype correlations, which are relevant for biomedical research [1]. Many inherited disorders of the nervous system are known in domestic animals including cattle [2]. Strong inbreeding in the bovine population has increased the risk of the occurrence of genetic diseases. The most common mode of transmission of genetic defects in cattle is monogenic autosomal recessive inheritance [2,3]. Calves with recessive defects are typically the consequence of inbreeding. This is common in livestock breeding programs when female descendants of artificial insemination sires are mated with test bulls that are direct descendents of the former sires. Most of the known recessive defects became apparent 5 to 10 generations after the founder animal, which corresponds to the time after which male and female descendants of the original carrier are mated. During the latent phase the deleterious allele might have been widely spread throughout the population explaining sudden outbreaks with many affected animals appearing simultaneously [3]

Methods

Results

Conclusion