In other species: taurine cattle

Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612123 (gene) , 251950 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific name: hereditary ataxia

Molecular basis: Abitbol et al. (2022) established monogenic autosomal recessive inheritance of the trait. The authors performed whole genome sequencing of an affected Australian Shepherd dog at 20x coverage. Subsequent to mapping and variant calling, homozygous private variants in the affected dog were filtered against 795 control genomes. This search revealed 10 homozygous private variants with SnpEff predicted high or moderate impact. Prioritization according to published functional knowledge identified a frameshift variant in PNPLA8 as the most likely candidate causative variant for the observed hereditary ataxia. PNPLA8 encoding a phospholipase presumably involved in mitochondrial lipid metabolism and essential for mitochondrial function was considered the top functional candidate gene as variants in this gene were already reported to cause comparable neurodegenerative diseases in humans, mice and cattle. The identified variant, PNPLA8:c.1169_1170dup, was predicted to induce a frameshift truncating roughly half of the PNPLA8 open reading frame, PNPLA8:p.(His391PhefsTer4). The authors found perfect genotype-phenotype association at this variant in 5 affected and 104 unaffected Australian Shepherds. The genotyped cohort included a medium-sized pedigree of related dogs, in which the expected co-segregation of genotypes with the disease was confirmed.

Clinical features: Abitbol et al. 2022 reported "The owners noticed the first signs between 4 and 19 months. They described hypermetria, bunny-hopping, wobbly and stiff gait on the pelvic limbs, and difficulties in walking up or down the stairs and in getting up. The initial neurological examination revealed moderate ataxia, more obvious on the pelvic limbs, with slight hypermetria and slight to no proprioceptive deficits on the pelvic limbs. Two of the five dogs showed discrete intention tremors. These signs suggested symmetrical cerebellar involvement. Motor deficits progressed toward the inability to walk without help from the age of 30 to 44 months. Neurological examination at this stage revealed non-ambulatory tetraparesis or tetraplegia. Severe spasticity of the hind limbs and proprioceptive deficits on all four limbs were present in all affected dogs. An absent menace-response was observed in two dogs. Neuroanatomical diagnosis was therefore suggestive of multifocal central nervous system damage. ... Four of the five affected dogs were euthanized between24 and 39 months of age."

Breed: Australian Shepherd (Dog) (VBO_0200095).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: