OMIA 002324-9615 : Epilepsy, mitochondrial dysfunction and neurodegeneration, PITRM1-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 618211

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: 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.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PITRM1 pitrilysin metallopeptidase 1 Canis lupus familiaris 2 NC_051806.1 (32565906..32602813) PITRM1 Homologene, Ensembl, NCBI gene

Variants

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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.

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
Parson Russell Terrier epilepsy, mitochondrial dysfunction and neurodegeneration PITRM1 deletion, small (<=20) CanFam3.1 2 g.32188565_32188570del c.175_180del p.(Leu59_Ser60del) ENSCAFT00000008673 c.175_180del 2021 33835239

Reference


2021 Hytönen, M.K., Sarviaho, R., Jackson, C.B., Syrjä, P., Jokinen, T., Matiasek, K., Rosati, M., Dallabona, C., Baruffini, E., Quintero, I., Arumilli, M., Monteuuis, G., Donner, J., Anttila, M., Suomalainen, A., Bindoff, L.A., Lohi, H. :
In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum Genet :, 2021. Pubmed reference: 33835239. DOI: 10.1007/s00439-021-02279-y.

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  • Created by Imke Tammen2 on 14 Apr 2021