title: Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide (G₄C₂) repeat expansion in C9orf72 gene.
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.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, Neurogenetics Department, University of Coimbra, Portugal. Electronic address: mralmeida2008@gmail.com.
authors.forename: Maria Rosário
authors.initials: MR
authors.lastname: Almeida
authors.affiliation: Neurology Department, Coimbra University Hospital, Coimbra, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Letra
authors.affiliation: Neurology Department, Hospital de Santo Espírito de Angra do Heroísmo, Azores, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Pires
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, Neurogenetics Department, University of Coimbra, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Santos
authors.affiliation: Neuropathology Laboratory, Neurology Department, Coimbra University Hospital, Portugal.
authors.forename: Olinda
authors.initials: O
authors.lastname: Rebelo
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, Neurogenetics Department, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, Neurogenetics Department, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, Neurogenetics Department, University of Coimbra, Portugal; Neurology Department, Coimbra University Hospital, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D057180:Frontotemporal Dementia / Q000150:complications / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D009154:Mutation; D010001:Osteitis Deformans / Q000150:complications / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D000071456:Sequestosome-1 Protein / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: C9orf72; Frontotemporal dementia; Paget disease of bone; SQSTM1