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Type of publication: Journal Article
Type of document: Full Paper

Year: 2011

Authors: Drögemüller, C; Reichart, U; Seuberlich, T; Oevermann, A; Baumgartner, M; Kühni Boghenbor, K; Stoffel, MH; Syring, C; Meylan, M; Müller, S; Müller, M; Gredler, B; Sölkner, J; Leeb, T

Title: An unusual splice defect in the mitofusin 2 gene (MFN2) is associated with degenerative axonopathy in Tyrolean Grey cattle.

Source: PLoS One. 2011; 6(4):e18931

Authors Vetmeduni Vienna:

Müller Mathias
Müller Simone
Reichart Ursula

Vetmed Research Units
Institute of Animal Breeding and Genetics

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.

Keywords Pubmed: Animals
Cattle Diseases/genetics*
Cattle Diseases/pathology
Chromosome Mapping
DNA Mutational Analysis
Gene Expression Regulation
Genetic Predisposition to Disease*
Genome-Wide Association Study
Inheritance Patterns/genetics
Mitochondrial Proteins/genetics*
Mitochondrial Proteins/metabolism
Molecular Sequence Data
Muscle Fibers, Skeletal/pathology
Muscle Fibers, Skeletal/ultrastructure
Nerve Degeneration/genetics*
Nerve Degeneration/pathology
RNA Splice Sites/genetics*
RNA, Messenger/genetics
RNA, Messenger/metabolism

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