OMIA 001954-9615 : Neurodegenerative vacuolar storage disease in Canis lupus familiaris

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Lagotto storage disease

Species-specific symbol: LSD

History: This disorder was first described by Kyöstilä et al. (2015).

Inheritance: LSD is inherited as a monogenic autosomal recessive trait. The age of onset varies and clinical symptoms appear at a mean age of 23 months with a range of approximately 4 months to 4 years. Kyöstilä et al. (2015) also noted incomplete penetrance as they encountered 3 out of 25 homozygous mutant dogs that did not show any clinical symptoms. These 3 dogs were 4, 7, and 12 years old at the time of the investigation.

Mapping: By conducting a linkage and homozygosity-mapping analysis, Kyöstilä et al. (2015) determined that the locus for this disorder is located in one of three regions on canine chromosomes 11, 13 and 20. Subsequent analysis of genome sequence in these three regions identified the causal mutation to be a C>T exchange on chromosome CFA20:50,618,958 (CanFam 3.1 assembly).

Molecular basis: Missense mutation: c.1288G>A; p.A430T; Chr20:50,618,958C>T (CanFam 3.1 assembly) (Kyöstilä et al., 2015)

Clinical features: As reported by Kyöstilä et al. (2015), "The typical clinical presentation in affected dogs was progressive ataxia". Neurological examination "revealed a mild to severe cerebellar ataxia . . . The majority of dogs had normal paw positioning responses when postural reactions were tested but showed delayed onset of correction in hopping reactions. Spinal reflexes were normal except for decreased or absent patellar reflexes in five dogs. Menace reaction was decreased in eight dogs, and exaggerated in one dog. Positional nystagmus was visible in four dogs during the eurological examination. Magnetic resonance imaging of the brain was performed in 11 affected dogs. The principal findings included signs of mild atrophy of the cerebellum in nine dogs and of the forebrain in six dogs. In five dogs, lateral ventricles were enlarged. A small corpus callosum was detected in three affected dogs when compared to age matched LRs. In two affected dogs, the brain imaging was unremarkable."

Pathology: As also reported by Kyöstilä et al. (2015), "Histological examination revealed widespread swelling and clear vacuolization of the neuronal cytoplasm, diffusely affecting the central and peripheral nervous system. The cytoplasmic vacuolization varied from fine vesiculation to large confluent vacuoles".

Syrjä et al. (2017) investigated the cellular alterations in detail and found that basal, but not induced autophagy, is altered in homozygous mutant cells from affected dogs.

Breed: Lagotto Romagnolo.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ATG4D autophagy related 4D, cysteine peptidase Canis lupus familiaris 20 NC_006602.3 (50623703..50618458) ATG4D 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
Lagotto Romagnolo Neurodegenerative vacuolar storage disease ATG4D missense CanFam3.1 20 g.50618958G>A c.1288G>A p.A430T 2015 25875846 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

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.
2017 Syrjä, P., Anwar, T., Jokinen, T., Kyöstilä, K., Jäderlund, K.H., Cozzi, F., Rohdin, C., Hahn, K., Wohlsein, P., Baumgärtner, W., Henke, D., Oevermann, A., Sukura, A., Leeb, T., Lohi, H., Eskelinen, E.L. :
Basal Autophagy Is Altered in Lagotto Romagnolo Dogs with an ATG4D Mutation. Vet Pathol :300985817712793, 2017. Pubmed reference: 28583040. DOI: 10.1177/0300985817712793.
2015 Kyöstilä, K., Syrjä, P., Jagannathan, V., Chandrasekar, G., Jokinen, T.S., Seppälä, E.H., Becker, D., Drögemüller, M., Dietschi, E., Drögemüller, C., Lang, J., Steffen, F., Rohdin, C., Jäderlund, K.H., Lappalainen, A.K., Hahn, K., Wohlsein, P., Baumgärtner, W., Henke, D., Oevermann, A., Kere, J., Lohi, H., Leeb, T. :
A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease. PLoS Genet 11:e1005169, 2015. Pubmed reference: 25875846. DOI: 10.1371/journal.pgen.1005169.

Edit History


  • Created by Frank Nicholas on 21 Apr 2015
  • Changed by Frank Nicholas on 21 Apr 2015
  • Changed by Tosso Leeb on 21 Apr 2015
  • Changed by Tosso Leeb on 16 Jun 2017