Cargando…
A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques
INTRODUCTION: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. RESULTS: We...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382926/ https://www.ncbi.nlm.nih.gov/pubmed/25853458 http://dx.doi.org/10.1186/s40478-015-0190-6 |
_version_ | 1782364646328500224 |
---|---|
author | Moreno, Fermin Rabinovici, Gil D Karydas, Anna Miller, Zachary Hsu, Sandy Chan Legati, Andrea Fong, Jamie Schonhaut, Daniel Esselmann, Hermann Watson, Christa Stephens, Melanie L Kramer, Joel Wiltfang, Jens Seeley, William W Miller, Bruce L Coppola, Giovanni Grinberg, Lea Tenenholz |
author_facet | Moreno, Fermin Rabinovici, Gil D Karydas, Anna Miller, Zachary Hsu, Sandy Chan Legati, Andrea Fong, Jamie Schonhaut, Daniel Esselmann, Hermann Watson, Christa Stephens, Melanie L Kramer, Joel Wiltfang, Jens Seeley, William W Miller, Bruce L Coppola, Giovanni Grinberg, Lea Tenenholz |
author_sort | Moreno, Fermin |
collection | PubMed |
description | INTRODUCTION: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. RESULTS: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. CONCLUSIONS: TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4382926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43829262015-04-03 A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques Moreno, Fermin Rabinovici, Gil D Karydas, Anna Miller, Zachary Hsu, Sandy Chan Legati, Andrea Fong, Jamie Schonhaut, Daniel Esselmann, Hermann Watson, Christa Stephens, Melanie L Kramer, Joel Wiltfang, Jens Seeley, William W Miller, Bruce L Coppola, Giovanni Grinberg, Lea Tenenholz Acta Neuropathol Commun Research INTRODUCTION: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. RESULTS: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. CONCLUSIONS: TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users. BioMed Central 2015-04-03 /pmc/articles/PMC4382926/ /pubmed/25853458 http://dx.doi.org/10.1186/s40478-015-0190-6 Text en © Moreno et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Moreno, Fermin Rabinovici, Gil D Karydas, Anna Miller, Zachary Hsu, Sandy Chan Legati, Andrea Fong, Jamie Schonhaut, Daniel Esselmann, Hermann Watson, Christa Stephens, Melanie L Kramer, Joel Wiltfang, Jens Seeley, William W Miller, Bruce L Coppola, Giovanni Grinberg, Lea Tenenholz A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
title | A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
title_full | A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
title_fullStr | A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
title_full_unstemmed | A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
title_short | A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
title_sort | novel mutation p112h in the tardbp gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382926/ https://www.ncbi.nlm.nih.gov/pubmed/25853458 http://dx.doi.org/10.1186/s40478-015-0190-6 |
work_keys_str_mv | AT morenofermin anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT rabinovicigild anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT karydasanna anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT millerzachary anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT hsusandychan anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT legatiandrea anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT fongjamie anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT schonhautdaniel anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT esselmannhermann anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT watsonchrista anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT stephensmelaniel anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT kramerjoel anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT wiltfangjens anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT seeleywilliamw anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT millerbrucel anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT coppolagiovanni anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT grinbergleatenenholz anovelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT morenofermin novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT rabinovicigild novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT karydasanna novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT millerzachary novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT hsusandychan novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT legatiandrea novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT fongjamie novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT schonhautdaniel novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT esselmannhermann novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT watsonchrista novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT stephensmelaniel novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT kramerjoel novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT wiltfangjens novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT seeleywilliamw novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT millerbrucel novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT coppolagiovanni novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques AT grinbergleatenenholz novelmutationp112hinthetardbpgeneassociatedwithfrontotemporallobardegenerationwithoutmotorneurondiseaseandabundantneuriticamyloidplaques |