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Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G4C2) repeat expansion in C9orf72 gene

Almeida, MR; Letra, L; Pires, P; Santos, A; Rebelo, O; Guerreiro, R; van der Zee, J; ... Santana, I; + view all (2016) Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G4C2) repeat expansion in C9orf72 gene. Neurobiology of Aging , 40 191.e1-191.e8. 10.1016/j.neurobiolaging.2015.12.015. Green open access

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Almedia et al Characterization of a FTLD-PDB family with the coexistence of SQSTM1 mutation and Hexanucleotide (G4C2) Repeat Expansion in C9orf72 gene .pdf

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Abstract

The C9orf72 expansion is considered a major genetic cause of familial frontotemporal dementia (FTD) in several patients' cohorts. Interestingly, C9orf72 expansion carriers, present also abundant neuronal p62-positive inclusions. Although p62/SQSTM1 mutations were initially associated with Paget disease of bone (PDB), they have been also identified in FTD. We describe an FTD-PDB family in which the proband presented with behavioral FTD phenotype and concomitant Paget disease. The molecular genetic analysis revealed the co-occurrence of 2 mutations; the pathogenic C9orf72 expansion and p.P392L heterozygous missense mutation in SQSTM1 gene. Amongst the 6 family members analyzed, the p.P392L SQSTM1 mutation segregated as expected with PDB, whereas the C9orf72 expansion segregated with frontal cognitive impairment or dementia in all but one carrier. The coexistence of these conditions could be underestimated since neither patients with FTD nor patients with PDB undergo bone scintigraphy or cognitive assessment, respectively. The number of cases with double mutations could also be over looked as the molecular strategy adopted in most laboratories ends with the identification of one pathogenic mutation in one of the known causative genes. Therefore, we advocate for further clinical and molecular evaluation in suspect cases.

Type: Article
Title: Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G4C2) repeat expansion in C9orf72 gene
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neurobiolaging.2015.12.015
Publisher version: http://dx.doi.org/10.1016/j.neurobiolaging.2015.12...
Language: English
Additional information: Copyright © 2016 Elsevier Inc. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/. The published version of record is available at http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.015
Keywords: C9orf72, Frontotemporal dementia, Paget disease of bone, SQSTM1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1479569
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