OMIA 002153-9615 : Neuroaxonal dystrophy, MFN2-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601152 , 617087 , 609260

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2011

Species-specific name: Fetal-onset neuroaxonal dystrophy

Species-specific symbol: FNAD

Species-specific description: Neuroaxonal dystrophy is a disorder of CNS development with motor neuron degeneration characterized by fetal-onset neuromuscular dysfunction causing joint contracture and respiratory failure at birth. Affected animals present with scoliosis, arthrogryposis, cerebellar, pulmonary, and spinal cord hypoplasia, respiratory failure, and thinning of the patellar tendon. The condition is lethal, and was first observed in a colony of laboratory dogs following the mating of a purebred Giant Schnauzer with a Beagle.

Edited by John C. Fyfe, D.V.M., Ph.D.

Mapping: Fyfe et al. (2011) mapped this disorder by linkage mapping with microsatellites to the telomeric end of chromosome CFA2.

Molecular basis: The likely causal variant is a 3 bp deletion in exon 14 of MFN2, the gene that codes for mitofusin 2. This c.1617_1619delGGA deletion is predicted to lead to the loss of a glutamate residue on the protein level, p.Q539del (Fyfe et al., 2011).

Clinical features: Signs include fetal akinesia, scoliosis, arthrogryposis, cerebellar hypoplasia, pulmonary hypoplasia, respiratory failure, thinning of the patellar tendon, and spinal cord hypoplasia. The condition is lethal (Fyfe et al., 2010).

Pathology: Mitofusin 2 is a multifunctional, membrane bound GTPase found in mitochondria and endoplasmic reticulum. It acts with mitofusin 1 to mediate fusion of the outer mitochondrial membrane. Alone, it mediates mitochondrial-ER contacts, autophagosome genesis, and mitochondrial transport in axons.

Affected dogs have very low levels of MFN2 in the brainstem, cerebrum, kidneys, and cultured fibroblasts. The defects are tissue-specific (Fyfe et al., 2011).

Histopathologic changes in affected dogs include swollen axons and spheroids in brainstem and spinal cord tracts, patchy loss of Purkinje cells, reduced cerebellar foliation, and multifocal thinning of the external granular cell layer.

Loss of neurons in the deep cerebellar nuclei, spheroids and loss of myelinated axons in spinal roots and peripheral nerves, increased apoptosis of skeletal muscle myocytes, and fibro-fatty connective tissue proliferation around joints can also be seen (Fyfe et al., 2010).

Prevalence: The condition has only been observed in a colony of laboratory dogs following the mating of a purebred Giant Schnauzer with a Beagle (Fyfe et al., 2010).

Control: Breeding of known carriers is not recommended. Siblings of affected dogs and dogs that have produced affected puppies should be tested for the causative mutation.

Breed: Schnauzer-Beagle cross.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MFN2 mitofusin 2 Canis lupus familiaris 2 NC_006584.3 (84310715..84284719) MFN2 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Schnauzer-Beagle cross Neuroaxonal dystrophy MFN2 deletion, small (<=20) c.1617_1619delGGA p.Q539del 2011 21643798

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2011 Fyfe, J.C., Al-Tamimi, R.A., Liu, J., Schäffer, A.A., Agarwala, R., Henthorn, P.S. :
A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy. Neurogenetics 12:223-32, 2011. Pubmed reference: 21643798. DOI: 10.1007/s10048-011-0285-6.
2010 Fyfe, JC., Al-Tamimi, RA., Castellani, RJ., Rosenstein, D., Goldowitz, D., Henthorn, PS. :
Inherited neuroaxonal dystrophy in dogs causing lethal, fetal-onset motor system dysfunction and cerebellar hypoplasia. J Comp Neurol 518:3771-84, 2010. Pubmed reference: 20653033. DOI: 10.1002/cne.22423.

Edit History


  • Created by Frank Nicholas on 29 Jun 2018
  • Changed by Frank Nicholas on 29 Jun 2018