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A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy

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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.

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Funding

This work was supported by the National Institutes of Health (NS41989, RR02512, and contract HV48141), the Purebred Dog Endowment Fund, College of Veterinary Medicine, Michigan State University, and in part by the Intramural Research Program of the NIH, NLM. Author RAA was supported by a Department of Pathology Scholarship for Basic Medical Sciences (KU-984) from the Kuwait University Faculty of Medicine.

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Authors and Affiliations

  1. Laboratory of Comparative Medical Genetics, Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA

    John C. Fyfe & Rabá A. Al-Tamimi

  2. Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Junlong Liu & Paula S. Henthorn

  3. National Center for Biotechnology Information, Department of Health and Human Services, National Institutes of Health, Bethesda, MD, 20894, USA

    Alejandro A. Schäffer & Richa Agarwala

  4. Laboratory of Comparative Medical Genetics, 2209 Biomedical Physical Sciences, Michigan State University, East Lansing, MI, 48824, USA

    John C. Fyfe

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  1. John C. Fyfe
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  2. Rabá A. Al-Tamimi
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  3. Junlong Liu
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  4. Alejandro A. Schäffer
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Correspondence to John C. Fyfe.

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Fyfe, J.C., Al-Tamimi, R.A., Liu, J. et al. A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy. Neurogenetics 12, 223–232 (2011). https://doi.org/10.1007/s10048-011-0285-6

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  • DOI: https://doi.org/10.1007/s10048-011-0285-6

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