title: An unusual splice defect in the mitofusin 2 gene (MFN2) is associated with degenerative axonopathy in Tyrolean Grey cattle.
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.
authors.affiliation: Institute of Genetics, University of Bern, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.forename: Ursula
authors.initials: U
authors.lastname: Reichart
authors.forename: Torsten
authors.initials: T
authors.lastname: Seuberlich
authors.forename: Anna
authors.initials: A
authors.lastname: Oevermann
authors.forename: Martin
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kühni  Boghenbor
authors.forename: Michael H
authors.initials: MH
authors.lastname: Stoffel
authors.forename: Claudia
authors.initials: C
authors.lastname: Syring
authors.forename: Mireille
authors.initials: M
authors.lastname: Meylan
authors.forename: Simone
authors.initials: S
authors.lastname: Müller
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Birgit
authors.initials: B
authors.lastname: Gredler
authors.forename: Johann
authors.initials: J
authors.lastname: Sölkner
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger