Publicaciones científicas

Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes

Thelen M(1), Razquin C(2), Hernández I(3), Gorostidi A(4), Sánchez-Valle R(5), Ortega-Cubero S(2), Wolfsgruber S(6), Drichel D(7), Fliessbach K(6), Duenkel T(8), Damian M(8), Heilmann S(9), Slotosch A(1), Lennarz M(1), Seijo-Martínez M(10), Rene R(11), Kornhuber J(12), Peters O(13), Luckhaus C(14), Jahn H(15), Hüll M(16), Rüther E(17), Wiltfang J(17), Lorenzo E(2), Gascon J(11), Lleó A(18), Lladó A(5), Campdelacreu J(11), Moreno F(19), Ahmadzadehfar H(20); Dementia Genetics Spanish Consortium (DEGESCO), Fortea J(18), Indakoetxea B(19), Heneka MT(21), Wetter A(22), Pastor MA(23), Riverol M(24), Becker T(25), Frölich L(8), Tárraga L(3), Boada M(3), Wagner M(6), Jessen F(6), Maier W(6), Clarimón J(18), López de Munain A(26), Ruiz A(3), Pastor P(27), Ramirez A(28).

(1) Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
(2) Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
(3) Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
(4) Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain.
(5) Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, IDIBAPS, Barcelona, Spain.
(6) Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
(7) German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
(8) Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
(9) Institute of Human Genetics, University of Bonn, Bonn, Germany.
(10) Department of Neurology, Hospital do Salnés, Pontevedra, Spain.
(11) Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain.
(12) Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
(13) Department of Psychiatry, Charité, Berlin, Germany.
(14) Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
(15) Department of Psychiatry, University of Hamburg, Hamburg, Germany.
(16) Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
(17) Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
(18) Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
(19) Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain; Department of Neurology, Donostia University Hospital, San Sebastian, Spain.
(20) Department of Nuclear Medicine, University of Bonn, Bonn, Germany.
(21) German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany.
(22) Department of Radiology, University of Essen, Essen, Germany.
(23) Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain; Neuroimaging Laboratory, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
(24) Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
(25) German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
(26) Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Neuroscience Area, BioDonostia Health Research Institute, San Sebastian, Spain; Department of Neurology, Donostia University Hospital, San Sebastian, Spain; Department of Neurosciences, University of Basque Country, San Sebastian, Spain.
(27) Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain; Center for Network Biomedical Research into Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
(28) Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany.

Revista: Neurobiology of Aging

Fecha: 01-nov-2014

Neurología

Resumen

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy.

The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]).

All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.

CITA DEL ARTÍCULO  Neurobiol Aging. 2014 Nov;35(11):2657.e13-9. doi: 10.1016/j.neurobiolaging.2014.06.018.

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