title: A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy.
abstract: We recently reported autosomal recessive fetal-onset neuroaxonal dystrophy (FNAD) in a large family of dogs that is not caused by mutation in the PLA2G6 locus (Fyfe et al., J Comp Neurol 518:3771-3784, 2010). Here, we report a genome-wide linkage analysis using 333 microsatellite markers to map canine FNAD to the telomeric end of chromosome 2. The interval of zero recombination was refined by single-nucleotide polymorphism (SNP) haplotype analysis to ~200 kb, and the included genes were sequenced. We found a homozygous 3-nucleotide deletion in exon 14 of mitofusin 2 (MFN2), predicting loss of a glutamate residue at position 539 in the protein of affected dogs. RT-PCR demonstrated near normal expression of the mutant mRNA, but MFN2 expression was undetectable to very low on western blots of affected dog brainstem, cerebrum, kidney, and cultured fibroblasts and by immunohistochemistry on brainstem sections. MFN2 is a multifunctional, membrane-bound GTPase of mitochondria and endoplasmic reticulum most commonly associated with human Charcot-Marie-Tooth disease type 2A2. The canine disorder extends the range of MFN2-associated phenotypes and suggests MFN2 as a candidate gene for rare cases of human FNAD.
authors.affiliation: Laboratory of Comparative Medical Genetics, Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. fyfe@cvm.msu.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Fyfe
authors.forename: Rabá A
authors.initials: RA
authors.lastname: Al-Tamimi
authors.forename: Junlong
authors.initials: J
authors.lastname: Liu
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Richa
authors.initials: R
authors.lastname: Agarwala
authors.forename: Paula S
authors.initials: PS
authors.lastname: Henthorn
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D004283:Dog Diseases / Q000453:epidemiology / Q000235:genetics*; D004285:Dogs; D005190:Family; D005315:Fetal Diseases / Q000453:epidemiology / Q000235:genetics* / Q000662:veterinary; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D019150:Neuroaxonal Dystrophies / Q000453:epidemiology / Q000235:genetics* / Q000662:veterinary; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases