The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics

Background The co-occurrence of the c.709-1G > A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these...

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Autores: Moreno Izco, Fermín, Indakoetxea Juanbeltz, Begoña, Barandiaran Amillano, Miryam, Caballero, María Cristina, Gorostidi, Ana, Calafell, Francesc, Gabilondo, Alazne, Tainta, Mikel, Zulaica, Miren, Martí Massó, José Félix, López de Munain Arregui, Adolfo José, Sánchez Juan, Pascual, Lee, Suzee E.
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/32666
Acceso en línea:http://hdl.handle.net/10810/32666
Access Level:acceso abierto
Palabra clave:frontotemporal lobar degeneration
C9orf72 repeat expansion
alzheimers-disease
progranulin mutation
dementia
Tau
variant
phenotypes
haplotype
spectrum
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spelling The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological CharacteristicsMoreno Izco, FermínIndakoetxea Juanbeltz, BegoñaBarandiaran Amillano, MiryamCaballero, María CristinaGorostidi, AnaCalafell, FrancescGabilondo, AlazneTainta, MikelZulaica, MirenMartí Massó, José FélixLópez de Munain Arregui, Adolfo JoséSánchez Juan, PascualLee, Suzee E.frontotemporal lobar degenerationC9orf72 repeat expansionalzheimers-diseaseprogranulin mutationdementiaTauvariantphenotypeshaplotypespectrumBackground The co-occurrence of the c.709-1G > A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. Methods and findings We compared clinical characteristics of 14 patients who carried the c.709-1G > A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G > A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T-patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked beta-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). Conclusions In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.F.M., P.S.J. and S.E.L. receive funding from the Tau Consortium. F.C. receives funding from the Generalitat de Catalunya (grant 2014 SGR 866). P.S.J. receives funding from ISCIII (PI12/02288). This work was also supported by the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Public Library Science201920192017info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/32666reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoIngléshttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178093info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Attribution 4.0 International (CC BY 4.0)Atribución 3.0 Españaoai:addi.ehu.eus:10810/326662026-06-18T09:23:17Z
dc.title.none.fl_str_mv The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
title The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
spellingShingle The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
Moreno Izco, Fermín
frontotemporal lobar degeneration
C9orf72 repeat expansion
alzheimers-disease
progranulin mutation
dementia
Tau
variant
phenotypes
haplotype
spectrum
title_short The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
title_full The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
title_fullStr The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
title_full_unstemmed The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
title_sort The Unexpected Co-Occurrence of GRN and MAPT p.A152T in Basque Families: Clinical and Pathological Characteristics
dc.creator.none.fl_str_mv Moreno Izco, Fermín
Indakoetxea Juanbeltz, Begoña
Barandiaran Amillano, Miryam
Caballero, María Cristina
Gorostidi, Ana
Calafell, Francesc
Gabilondo, Alazne
Tainta, Mikel
Zulaica, Miren
Martí Massó, José Félix
López de Munain Arregui, Adolfo José
Sánchez Juan, Pascual
Lee, Suzee E.
author Moreno Izco, Fermín
author_facet Moreno Izco, Fermín
Indakoetxea Juanbeltz, Begoña
Barandiaran Amillano, Miryam
Caballero, María Cristina
Gorostidi, Ana
Calafell, Francesc
Gabilondo, Alazne
Tainta, Mikel
Zulaica, Miren
Martí Massó, José Félix
López de Munain Arregui, Adolfo José
Sánchez Juan, Pascual
Lee, Suzee E.
author_role author
author2 Indakoetxea Juanbeltz, Begoña
Barandiaran Amillano, Miryam
Caballero, María Cristina
Gorostidi, Ana
Calafell, Francesc
Gabilondo, Alazne
Tainta, Mikel
Zulaica, Miren
Martí Massó, José Félix
López de Munain Arregui, Adolfo José
Sánchez Juan, Pascual
Lee, Suzee E.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv frontotemporal lobar degeneration
C9orf72 repeat expansion
alzheimers-disease
progranulin mutation
dementia
Tau
variant
phenotypes
haplotype
spectrum
topic frontotemporal lobar degeneration
C9orf72 repeat expansion
alzheimers-disease
progranulin mutation
dementia
Tau
variant
phenotypes
haplotype
spectrum
description Background The co-occurrence of the c.709-1G > A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. Methods and findings We compared clinical characteristics of 14 patients who carried the c.709-1G > A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G > A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T-patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked beta-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). Conclusions In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.
publishDate 2017
dc.date.none.fl_str_mv 2017
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/32666
url http://hdl.handle.net/10810/32666
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178093
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library Science
publisher.none.fl_str_mv Public Library Science
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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