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The disease started with epileptic seizures at 6\u201312\u00a0weeks of age and progressed rapidly to\n                    <jats:italic>status epilepticus<\/jats:italic>\n                    and death or euthanasia. 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-\u03b2 (A\u03b2). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (\n                    <jats:italic>PITRM1<\/jats:italic>\n                    ) 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, potentially affecting protein folding and function. 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. Loss-of-function variants in human\n                    <jats:italic>PITRM1<\/jats:italic>\n                    result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous\n                    <jats:italic>Pitrm1<\/jats:italic>\n                    -knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and A\u03b2 deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, A\u03b2 accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.\n                  <\/jats:p>","DOI":"10.1007\/s00439-021-02279-y","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T03:03:16Z","timestamp":1617937396000},"page":"1593-1609","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration"],"prefix":"10.1007","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1976-5874","authenticated-orcid":false,"given":"Marjo K.","family":"Hyt\u00f6nen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riika","family":"Sarviaho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1035-6417","authenticated-orcid":false,"given":"Christopher B.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-2636","authenticated-orcid":false,"given":"Pernilla","family":"Syrj\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-0109","authenticated-orcid":false,"given":"Tarja","family":"Jokinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5021-3280","authenticated-orcid":false,"given":"Kaspar","family":"Matiasek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1485-1610","authenticated-orcid":false,"given":"Marco","family":"Rosati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4397-9143","authenticated-orcid":false,"given":"Cristina","family":"Dallabona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8280-7849","authenticated-orcid":false,"given":"Enrico","family":"Baruffini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-1289","authenticated-orcid":false,"given":"Ileana","family":"Quintero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4072-0996","authenticated-orcid":false,"given":"Meharji","family":"Arumilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7193-7771","authenticated-orcid":false,"given":"Geoffray","family":"Monteuuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9874-8484","authenticated-orcid":false,"given":"Jonas","family":"Donner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4089-1357","authenticated-orcid":false,"given":"Marjukka","family":"Anttila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4833-5195","authenticated-orcid":false,"given":"Anu","family":"Suomalainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0988-276X","authenticated-orcid":false,"given":"Laurence A.","family":"Bindoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1087-5532","authenticated-orcid":false,"given":"Hannes","family":"Lohi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"2279_CR1","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3233\/JAD-2011-101716","volume":"27","author":"N Alikhani","year":"2011","unstructured":"Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS (2011a) Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer\u2019s disease brain mitochondria. 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JD is an employee of Genoscoper Laboratories Ltd.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Sample collection was ethically approved by the Animal Ethics Committee of State Provincial Office of Southern Finland (ESAVI\/343\/04.10.07\/2016 and ESAVI\/25696\/2020).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Written consent was given by the dogs\u2019 owners who donated samples from their dogs.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The recorder has provided a written permission to publish the video recordings (Online Resource 2 and 3) under the terms of Creative Commons Attribution 4.0 International License.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}