In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration

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http://hdl.handle.net/10138/335667

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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 2021 , ' In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration ' , Human Genetics , vol. 140 , pp. 1593-1609 . https://doi.org/10.1007/s00439-021-02279-y

Title: In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
Author: Hytönen, Marjo K.; Sarviaho, Riika; Jackson, Christopher B.; Syrjä, Pernilla; Jokinen, Tarja; Matiasek, Kaspar; Rosati, Marco; Dallabona, Cristina; Baruffini, Enrico; Quintero, Ileana; Arumilli, Meharji; Monteuuis, Geoffray; Donner, Jonas; Anttila, Marjukka; Suomalainen, Anu; Bindoff, Laurence A.; Lohi, Hannes
Other contributor: University of Helsinki, Medicum
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Department of Biochemistry and Developmental Biology
University of Helsinki, Veterinary Pathology and Parasitology
University of Helsinki, Helsinki One Health (HOH)
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Biochemistry and Developmental Biology
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Helsinki One Health (HOH)

















Date: 2021
Language: eng
Number of pages: 17
Belongs to series: Human Genetics
ISSN: 0340-6717
DOI: https://doi.org/10.1007/s00439-021-02279-y
URI: http://hdl.handle.net/10138/335667
Abstract: We investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6-12 weeks of age and progressed rapidly to status epilepticus 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-beta (A beta). 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, 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 PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and A beta deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, A beta accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.
Subject: 1184 Genetics, developmental biology, physiology
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