caa a22 4500 445364556 CHVBK 20180317142925.0 cr unu---uuuuu 170323e20110801xx s 000 0 eng 10.1007/s10048-011-0285-6 doi (NATIONALLICENCE)springer-10.1007/s10048-011-0285-6 A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy [Elektronische Daten] [John Fyfe, Rabá Al-Tamimi, Junlong Liu, Alejandro Schäffer, Richa Agarwala, Paula Henthorn] 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 ~200kb, 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. Springer-Verlag (outside the USA), 2011 Neuroaxonal dystrophy nationallicence Mitofusin 2 nationallicence Linkage analysis nationallicence Animal model nationallicence Disease gene nationallicence Fyfe John Laboratory of Comparative Medical Genetics, Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, 48824, East Lansing, MI, USA aut Al-Tamimi Rabá Laboratory of Comparative Medical Genetics, Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, 48824, East Lansing, MI, USA aut Liu Junlong Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA aut Schäffer Alejandro National Center for Biotechnology Information, Department of Health and Human Services, National Institutes of Health, 20894, Bethesda, MD, USA aut Agarwala Richa National Center for Biotechnology Information, Department of Health and Human Services, National Institutes of Health, 20894, Bethesda, MD, USA aut Henthorn Paula Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA aut neurogenetics Springer-Verlag 12/3(2011-08-01), 223-232 1364-6745 12:3<223 2011 12 10048 https://doi.org/10.1007/s10048-011-0285-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10048-011-0285-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fyfe John Laboratory of Comparative Medical Genetics, Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, 48824, East Lansing, MI, USA aut NATIONALLICENCE 700 1- Al-Tamimi Rabá Laboratory of Comparative Medical Genetics, Department of Microbiology and Molecular Genetics, College of Veterinary Medicine, Michigan State University, 48824, East Lansing, MI, USA aut NATIONALLICENCE 700 1- Liu Junlong Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA aut NATIONALLICENCE 700 1- Schäffer Alejandro National Center for Biotechnology Information, Department of Health and Human Services, National Institutes of Health, 20894, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Agarwala Richa National Center for Biotechnology Information, Department of Health and Human Services, National Institutes of Health, 20894, Bethesda, MD, USA aut NATIONALLICENCE 700 1- Henthorn Paula Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA aut NATIONALLICENCE 773 0- neurogenetics Springer-Verlag 12/3(2011-08-01), 223-232 1364-6745 12:3<223 2011 12 10048 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer