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

Characterization of an FTLD-PDB family with the coexistence of SQSTM1 mutation and hexanucleotide... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurobiology of Aging Elsevier

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

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Publisher
Elsevier
Copyright
Copyright © 2016 Elsevier Inc.
ISSN
0197-4580
D.O.I.
10.1016/j.neurobiolaging.2015.12.015
Publisher site
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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.

Journal

Neurobiology of AgingElsevier

Published: Apr 1, 2016

References

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  • Characterization of a non-UBA domain missense mutation of sequestosome 1 (SQSTM1) in Paget's disease of bone
    Najat, D.; Garner, T.; Hagen, T.; Shaw, B.; Sheppard, P.W.; Falchetti, A.; Marini, F.; Brandi, M.L.; Long, J.E.; Cavey, J.R.; Searle, M.S.; Layfield, R.
  • Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson's disease
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