10.1371/journal.pone.0018931 Cord Drögemüller Cord Drögemüller Ursula Reichart Ursula Reichart Torsten Seuberlich Torsten Seuberlich Anna Oevermann Anna Oevermann Martin Baumgartner Martin Baumgartner Kathrin Kühni Boghenbor Kathrin Kühni Boghenbor Michael H. Stoffel Michael H. Stoffel Claudia Syring Claudia Syring Mireille Meylan Mireille Meylan Simone Müller Simone Müller Mathias Müller Mathias Müller Birgit Gredler Birgit Gredler Johann Sölkner Johann Sölkner Tosso Leeb Tosso Leeb An Unusual Splice Defect in the Mitofusin 2 Gene (<i>MFN2</i>) Is Associated with Degenerative Axonopathy in Tyrolean Grey Cattle Public Library of Science 2011 Tyrolean Grey Cattle Tyrolean Grey cattle monogenic autosomal recessive inheritance Mitofusin 2 Gene MFN 2 transcript SNP CMT Charcot-Marie-Tooth disease -2A Unusual Splice Defect Tyrolean Grey cattle 1.9 Mb interval mitochondrial membrane protein MFN 2 gene control Tyrolean Grey cattle exonic splice enhancer MFN 2 CNS MFN 2 mutations ESE 2011-04-15 02:05:14 Dataset https://plos.figshare.com/articles/dataset/An_Unusual_Splice_Defect_in_the_Mitofusin_2_Gene_MFN2_Is_Associated_with_Degenerative_Axonopathy_in_Tyrolean_Grey_Cattle/137514 <div><p>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 <i>MFN2</i> 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 <i>MFN2</i> mutations. Therefore, we considered <i>MFN2</i> 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 <i>MFN2</i> 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 <i>MFN2</i> 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.</p></div>