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

Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 601152 (trait) , 617087 (trait) , 609260 (trait) , 608507 (gene)

Links to MONDO diseases: No links.

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).

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

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 (Dog) (VBO_0201186).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MFN2 mitofusin 2 Canis lupus familiaris 2 NC_051806.1 (84971271..84945233) MFN2 Homologene, Ensembl , NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
472 Schnauzer-Beagle Cross (Dog) Neuroaxonal dystrophy MFN2 deletion, small (<=20) Naturally occurring variant CanFam3.1 2 g.84289962_84289964del c.1617_1619del p.(E539del) NM_001284441.1; NP_001271370.1; published as c.1617_1619delGGA; genomic position considers 3' rule of the HGVS 2011 21643798 Genomic position in CanFam3.1 provided by Robert Kuhn.

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2018). OMIA:002153-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70

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