Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 611340 (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: 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.

In a study aimed "to clarify the origin of the limiting membrane of the accumulating vacuoles and determine whether altered basal autophagy affects the extracellular release of vesicles in cells from diseased dogs" Syrjä et al. (2020) concluded that "An increased release of extracellular vesicles may serve as a compensatory mechanism in disposal of intracellular proteins during dysfunctional basal autophagy in this spontaneous disease."

Breed: Lagotto Romagnolo.
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: