Categories: Behaviour / neurological phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 618211 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Inheritance: Hytönen et al. (2021): "Relatedness information of the affected dogs suggested an autosomal recessive mode of inheritance for the disease as all affected dogs were closely related, including affected littermates, both sexes were affected, and parents were unaffected."

Molecular basis: Hytönen et al. (2021): "Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1 ... . Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity."

Clinical features: Hytönen et al. (2021): "The affected dogs develop normally until 6–12 weeks of life before the onset of rapidly worsening seizures, status epilepticus, and death."

Pathology: Hytönen et al. (2021): "Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ)."

Breed: Parson Russell Terrier (Dog) (VBO_0200987).
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: