Miguel Tábuas-Pereira1,2,3, Isabel Santana1,2,3,4, Maria Rosário Almeida4, João Durães1,3, Marisa Lima1,4, Diana Duro1,4, Célia Kun-Rodrigues5, Jose Bras5,6, Rita Guerreiro5,6. 1. Neurology Department, University Hospital of Coimbra, Coimbra, Portugal. 2. Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 3. Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. 4. CNC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. 5. Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA. 6. Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.
Abstract
BACKGROUND AND PURPOSE: TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. METHODS: We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). RESULTS: Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. CONCLUSION: We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.
BACKGROUND AND PURPOSE: TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. METHODS: We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). RESULTS: Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. CONCLUSION: We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.
Authors: M L Gorno-Tempini; A E Hillis; S Weintraub; A Kertesz; M Mendez; S F Cappa; J M Ogar; J D Rohrer; S Black; B F Boeve; F Manes; N F Dronkers; R Vandenberghe; K Rascovsky; K Patterson; B L Miller; D S Knopman; J R Hodges; M M Mesulam; M Grossman Journal: Neurology Date: 2011-02-16 Impact factor: 9.910
Authors: Ivan A Adzhubei; Steffen Schmidt; Leonid Peshkin; Vasily E Ramensky; Anna Gerasimova; Peer Bork; Alexey S Kondrashov; Shamil R Sunyaev Journal: Nat Methods Date: 2010-04 Impact factor: 28.547
Authors: Katya Rascovsky; John R Hodges; David Knopman; Mario F Mendez; Joel H Kramer; John Neuhaus; John C van Swieten; Harro Seelaar; Elise G P Dopper; Chiadi U Onyike; Argye E Hillis; Keith A Josephs; Bradley F Boeve; Andrew Kertesz; William W Seeley; Katherine P Rankin; Julene K Johnson; Maria-Luisa Gorno-Tempini; Howard Rosen; Caroline E Prioleau-Latham; Albert Lee; Christopher M Kipps; Patricia Lillo; Olivier Piguet; Jonathan D Rohrer; Martin N Rossor; Jason D Warren; Nick C Fox; Douglas Galasko; David P Salmon; Sandra E Black; Marsel Mesulam; Sandra Weintraub; Brad C Dickerson; Janine Diehl-Schmid; Florence Pasquier; Vincent Deramecourt; Florence Lebert; Yolande Pijnenburg; Tiffany W Chow; Facundo Manes; Jordan Grafman; Stefano F Cappa; Morris Freedman; Murray Grossman; Bruce L Miller Journal: Brain Date: 2011-08-02 Impact factor: 13.501
Authors: Rita Guerreiro; Elizabeth Gibbons; Miguel Tábuas-Pereira; Celia Kun-Rodrigues; Gustavo C Santo; Jose Bras Journal: Neurobiol Dis Date: 2020-05-19 Impact factor: 5.996