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

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 euth...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519929/
https://www.ncbi.nlm.nih.gov/pubmed/33835239
http://dx.doi.org/10.1007/s00439-021-02279-y
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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
author_facet 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
author_sort Hytönen, Marjo K.
collection PubMed
description 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-β (Aβ). 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 Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02279-y.
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spelling pubmed-85199292021-10-29 In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration 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 Hum Genet Original Investigation 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-β (Aβ). 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 Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02279-y. Springer Berlin Heidelberg 2021-04-09 2021 /pmc/articles/PMC8519929/ /pubmed/33835239 http://dx.doi.org/10.1007/s00439-021-02279-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Investigation
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
In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
title In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
title_full In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
title_fullStr In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
title_full_unstemmed In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
title_short In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
title_sort in-frame deletion in canine pitrm1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519929/
https://www.ncbi.nlm.nih.gov/pubmed/33835239
http://dx.doi.org/10.1007/s00439-021-02279-y
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