TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy

Michael A. Gitcho, Eileen H. Bigio, Manjari Mishra, Nancy Johnson, Sandra Weintraub, Marsel Mesulam, Rosa Rademakers, Sumi Chakraverty, Carlos Cruchaga, John C. Morris, Alison M. Goate, Nigel J. Cairns

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3′-untranslated region (3′-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3′-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.

Original languageEnglish (US)
Pages (from-to)633-645
Number of pages13
JournalActa neuropathologica
Volume118
Issue number5
DOIs
StatePublished - Nov 2009

Keywords

  • 3′-Untranslated region
  • Amyotrophic lateral sclerosis
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Motor neuron disease
  • TARDBP
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Gitcho, M. A., Bigio, E. H., Mishra, M., Johnson, N., Weintraub, S., Mesulam, M., Rademakers, R., Chakraverty, S., Cruchaga, C., Morris, J. C., Goate, A. M., & Cairns, N. J. (2009). TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. Acta neuropathologica, 118(5), 633-645. https://doi.org/10.1007/s00401-009-0571-7